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1.
Cancer Lett ; 392: 51-59, 2017 04 28.
Article in English | MEDLINE | ID: mdl-28153789

ABSTRACT

Mitogen-activated protein kinases (MAPKs) regulate diverse cellular processes including proliferation, cell survival, differentiation, and apoptosis. While conventional MAPK constituents have well-defined roles in oncogenesis, the MEK5 pathway has only recently emerged in cancer research. In this review, we consider the MEK5 signaling cascade, focusing specifically on its involvement in drug resistance and regulation of aggressive cancer phenotypes. Moreover, we explore the role of MEK5/ERK5 in tumorigenesis and metastatic progression, discussing the discrepancies in preclinical studies and assessing its viability as a therapeutic target for anti-cancer agents.


Subject(s)
MAP Kinase Kinase 5/metabolism , Mitogen-Activated Protein Kinase 7/metabolism , Neoplasms/metabolism , Proto-Oncogene Proteins/metabolism , Signal Transduction , Animals , Antineoplastic Agents/therapeutic use , Apoptosis , Cell Differentiation , Cell Proliferation , Drug Resistance, Neoplasm , Humans , MAP Kinase Kinase 5/antagonists & inhibitors , MAP Kinase Kinase 5/genetics , Molecular Targeted Therapy , Mutation , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins/genetics , Signal Transduction/drug effects
2.
Pharmacol Rep ; 66(1): 174-8, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24905325

ABSTRACT

BACKGROUND: Endogenous sphingolipid signaling has been shown to play an important role in prostate cancer endocrine resistance. METHODS: The novel SphK2 inhibitor, ABC294640, was used to explore SphK signaling in androgen resistant prostate cancer cell death signaling. RESULTS: It dose-dependently decreased PC-3 and LNCaP cell viability, IC(50) of 28 ± 6.1 µM (p < 0.05) and 25 ± 4.0 µM (p < 0.05), respectively. ABC294640 was more potent in long-term clonogenic survival assays; IC(50) of 14 ± 0.4 µM (p < 0.05) in PC-3 cells and 12 ± 0.9 µM (p < 0.05) in LNCaP cells. Intrinsic apoptotic assays failed to demonstrate increased caspase-9 activity. Ki-67 staining demonstrated decreased proliferation by 50 ± 8.4% (p < 0.01) in PC-3 cells. CONCLUSIONS: SphK2 inhibition decreases androgen resistant prostate cancer viability, survival, and proliferation independently of the intrinsic apoptotic pathway. Findings are in contrast to recent observations of ABC29460 acting dependently on the intrinsic pathway in other endocrine resistant cancer cell lines.


Subject(s)
Adamantane/analogs & derivatives , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Prostatic Neoplasms/drug therapy , Pyridines/pharmacology , Adamantane/pharmacology , Androgen Antagonists/therapeutic use , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Resistance, Neoplasm , Humans , Ki-67 Antigen/analysis , Male , Phosphotransferases (Alcohol Group Acceptor)/physiology , Prostatic Neoplasms/pathology
3.
Bioorg Med Chem ; 22(4): 1412-20, 2014 Feb 15.
Article in English | MEDLINE | ID: mdl-24457089

ABSTRACT

Multidrug-resistance is a major cause of cancer chemotherapy failure in clinical treatment. Evidence shows that multidrug-resistant cancer cells are as sensitive as corresponding regular cancer cells under the exposure to anticancer ceramide analogs. In this work we designed five new ceramide analogs with different backbones, in order to test the hypothesis that extending the conjugated system in ceramide analogs would lead to an increase of their anticancer activity and selectivity towards resistant cancer cells. The analogs with the 3-ketone-4,6-diene backbone show the highest apoptosis-inducing efficacy. The most potent compound, analog 406, possesses higher pro-apoptotic activity in chemo-resistant cell lines MCF-7TN-R and NCI/ADR-RES than the corresponding chemo-sensitive cell lines MCF-7 and OVCAR-8, respectively. However, this compound shows the same potency in inhibiting the growth of another pair of chemo-sensitive and chemo-resistant cancer cells, MCF-7 and MCF-7/Dox. Mechanism investigations indicate that analog 406 can induce apoptosis in chemo-resistant cancer cells through the mitochondrial pathway. Cellular glucosylceramide synthase assay shows that analog 406 does not interrupt glucosylceramide synthase in chemo-resistant cancer cell NCI/ADR-RES. These findings suggest that due to certain intrinsic properties, ceramide analogs' pro-apoptotic activity is not disrupted by the normal drug-resistance mechanisms, leading to their potential use for overcoming cancer multidrug-resistance.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzeneacetamides/chemistry , Ceramides/chemistry , Ceramides/pharmacology , Ketones/chemistry , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Benzeneacetamides/chemical synthesis , Benzeneacetamides/pharmacology , Cell Line, Tumor , Ceramides/chemical synthesis , Drug Resistance, Neoplasm/drug effects , Glucosyltransferases/antagonists & inhibitors , Glucosyltransferases/metabolism , Humans , Isomerism , MCF-7 Cells , Molecular Conformation
4.
Mol Carcinog ; 53(1): 38-48, 2014 Jan.
Article in English | MEDLINE | ID: mdl-22911661

ABSTRACT

microRNAs (miRNA) are regulators of cellular pathways and alterations of normal miRNA expression levels have been shown to increase tumorigenesis. miR-24 has been demonstrated as having both tumor suppressive and oncogenic properties depending on cell context. Here, we demonstrate a possible role for pre-miR-24-2 as a tumor suppressor in the MCF-7 breast cancer cell line through the preferential processing of mature miR-24-2* over miR-24. Specifically, we show that the ectopic expression of miR-24-2* in MCF-7 breast cancer cells results in a suppression of cellular survival both in vivo and in vitro. Notably, the overexpression of miR-24-2* results in a dampening of cell survival through the targeted suppression of PKCα. In addition, a similar biological change is observed in vivo where MCF-7 cells overexpressing pre-miR-24-2 have decreased tumorigenicity and tumor incidence. Taken together our data demonstrate that when overexpressed biogenesis of the pre-miR-24-2 favors miR-24-2* in the MCF-7 breast cancer cell line and suggests a tumor suppressive role for miR-24-2* observed through the inhibition of PKCα-mediated cellular survival.


Subject(s)
Breast Neoplasms/genetics , MicroRNAs/genetics , Protein Kinase C-alpha/genetics , Animals , Base Pairing , Base Sequence , Binding Sites , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Survival/genetics , Cell Transformation, Neoplastic/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Isoenzymes , MCF-7 Cells , Mice , MicroRNAs/chemistry , MicroRNAs/metabolism , Protein Kinase C-alpha/chemistry , Protein Kinase C-alpha/metabolism , RNA Interference
5.
Anticancer Res ; 33(9): 3573-9, 2013 Sep.
Article in English | MEDLINE | ID: mdl-24023282

ABSTRACT

ABC294640, a selective inhibitor of sphingosine kinase-2, inhibits the formation of sphingosine 1-phosphate (S1P), a signaling lipid implicated in promoting tumor survival. We investigated the anticancer activity of ABC294640 in two ovarian cancer cell lines, BG-1 and Caov-3. ABC294640 dose-dependently inhibited clonogenic survival and cell viability of both ovarian cancer lines in vitro. Using enzyme-linked immunosorbant assays and western blot detection in chemoresistant Caov-3 cells, treatment with ABC294640 alone also potentiated bcl-2-associated X-protein and caspase-9 transcription levels, although it did not significantly increase apoptotic cell death. Interestingly, ABC294640 administered to Caov-3 ovarian cancer cells in conjunction with paclitaxel induced apoptotic cell death through activation of caspase-9. Induction of apoptosis may mediate the anticancer effect of ABC294640 in ovarian cancer, although its precise antitumor mechanism is unclear. Ultimately, through its inhibition of S1P formation and subsequent effects on critical survival signaling cascades, ABC294640 may prove to be a useful adjunct to help re-sensitize tumors to standard therapy.


Subject(s)
Adamantane/analogs & derivatives , Antineoplastic Agents/therapeutic use , Drug Resistance, Neoplasm , Ovarian Neoplasms/drug therapy , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Pyridines/therapeutic use , Adamantane/pharmacology , Adamantane/therapeutic use , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Female , Humans , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/pathology , Pyridines/pharmacology , bcl-2-Associated X Protein/metabolism
6.
PLoS One ; 8(8): e69291, 2013.
Article in English | MEDLINE | ID: mdl-23950888

ABSTRACT

Endocrine resistance and metastatic progression are primary causes of treatment failure in breast cancer. While mitogen activated protein kinases (MAPKs) are known to promote ligand-independent cell growth, the role of the MEK5-ERK5 pathway in the progression of clinical breast carcinoma remains poorly understood. Here, we demonstrated increased ERK5 activation in 30 of 39 (76.9%) clinical tumor samples, as well as across breast cancer cell systems. Overexpression of MEK5 in MCF-7 cells promoted both hormone-dependent and hormone-independent tumorigenesis in vitro and in vivo and conferred endocrine therapy resistance to previously sensitive breast cancer cells. Expression of MEK5 suppressed estrogen receptor (ER)α, but not ER-ß protein levels, and abrogated downstream estrogen response element (ERE) transcriptional activity and ER-mediated gene transcription. Global gene expression changes associated with upregulation of MEK5 included increased activation of ER-α independent growth signaling pathways and promotion of epithelial-to-mesenchymal transition (EMT) markers. Taken together, our findings show that the MEK5-ERK5 pathway mediates progression to an ER(-), mesenchymal and endocrine therapy resistant phenotype. Given the need for new clinical therapeutic targets, our results demonstrate the therapeutic potential of targeting the MEK5-ERK5 pathway in breast cancer.


Subject(s)
Breast Neoplasms/genetics , Carcinoma/genetics , Estrogen Receptor alpha/genetics , Gene Expression Regulation, Neoplastic , MAP Kinase Kinase 5/genetics , Mitogen-Activated Protein Kinase 7/genetics , Animals , Antineoplastic Agents, Hormonal/pharmacology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carcinogenesis/genetics , Carcinogenesis/metabolism , Carcinogenesis/pathology , Carcinoma/metabolism , Carcinoma/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Epithelial-Mesenchymal Transition/genetics , Estradiol/analogs & derivatives , Estradiol/pharmacology , Estrogen Receptor alpha/metabolism , Estrogens/metabolism , Female , Fulvestrant , Gene Expression Profiling , Humans , MAP Kinase Kinase 5/metabolism , Mice , Mitogen-Activated Protein Kinase 7/antagonists & inhibitors , Mitogen-Activated Protein Kinase 7/metabolism , Neoplasms, Experimental , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Signal Transduction
7.
Future Med Chem ; 5(12): 1405-21, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23919551

ABSTRACT

Ceramide serves as a central mediator in sphingolipid metabolism and signaling pathways, regulating many fundamental cellular responses. It is referred to as a 'tumor suppressor lipid', since it powerfully potentiates signaling events that drive apoptosis, cell cycle arrest, and autophagic responses. In the typical cancer cell, ceramide levels and signaling are usually suppressed by overexpression of ceramide-metabolizing enzymes or downregulation of ceramide-generating enzymes. However, chemotherapeutic drugs as well as radiotherapy increase intracellular ceramide levels, while exogenously treating cancer cells with short-chain ceramides leads to anticancer effects. All evidence currently points to the fact that the upregulation of ceramide levels is a promising anticancer strategy. In this review, we exhibit many anticancer ceramide analogs as downstream receptor agonists and ceramide-metabolizing enzyme inhibitors.


Subject(s)
Antineoplastic Agents/chemistry , Ceramides/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Ceramidases/antagonists & inhibitors , Ceramidases/metabolism , Ceramides/pharmacology , Ceramides/therapeutic use , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Glucosyltransferases/antagonists & inhibitors , Glucosyltransferases/metabolism , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Signal Transduction/drug effects , Structure-Activity Relationship
8.
Exp Biol Med (Maywood) ; 237(7): 832-44, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22859737

ABSTRACT

Sphingosine kinase signaling has become of increasing interest as a cancer target in recent years. Two sphingosine kinase inhibitors, sphingosine kinase inhibitor (SKI)-II and ABC294640, are promising as potential breast cancer therapies. However, evidence for their therapeutic properties in specific breast cancer subtypes is currently lacking. In this study, we characterize these drugs in luminal, endocrine-resistant (MDA-MB-361) and basal-A, triple-negative (MDA-MB-468) breast cancer cells and compare them with previously published data in other breast cancer cell models. Both SKI-II and ABC294640 demonstrated greater efficacy in basal-A compared with luminal breast cancer. ABC294640, in particular, induced apoptosis and blocked proliferation both in vitro and in vivo in this triple-negative breast cancer system. Furthermore, Sphk expression promotes survival and endocrine therapy resistance in previously sensitive breast cancer cells. Taken together, these results characterize sphingosine kinase inhibitors across breast cancer cell systems and demonstrate their therapeutic potential as anti-cancer agents.


Subject(s)
Breast Neoplasms/drug therapy , Enzyme Inhibitors/pharmacology , Isoenzymes/drug effects , Phosphotransferases (Alcohol Group Acceptor)/drug effects , Adamantane/analogs & derivatives , Adamantane/pharmacology , Adamantane/therapeutic use , Aminophenols/pharmacology , Aminophenols/therapeutic use , Animals , Antineoplastic Agents, Hormonal/therapeutic use , Base Sequence , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Cell Line, Tumor , DNA Primers , Drug Resistance, Neoplasm , Enzyme Inhibitors/therapeutic use , Enzyme-Linked Immunosorbent Assay , Female , Humans , Mice , Mice, Nude , Mice, SCID , Pyridines/pharmacology , Pyridines/therapeutic use , Real-Time Polymerase Chain Reaction , Receptors, Estrogen/metabolism , Thiazoles/pharmacology , Thiazoles/therapeutic use , Xenograft Model Antitumor Assays
9.
Sci Rep ; 2: 539, 2012.
Article in English | MEDLINE | ID: mdl-22844580

ABSTRACT

Altered death receptor signaling and resistance to subsequent apoptosis is an important clinical resistance mechanism. Here, we investigated the role of death receptor resistance in breast cancer progression. Resistance of the estrogen receptor alpha (ER)-positive, chemosensitive MCF7 breast cancer cell line to tumor necrosis factor (TNF) was associated with loss of ER expression and a multi-drug resistant phenotype. Changes in three major pathways were involved in this transition to a multidrug resistance phenotype: ER, Death Receptor and epithelial to mesenchymal transition (EMT). Resistant cells exhibited altered ER signaling, resulting in decreased ER target gene expression. The death receptor pathway was significantly altered, blocking extrinsic apoptosis and increasing NF-kappaB survival signaling. TNF resistance promoted EMT changes, resulting in a more aggressive phenotype. This first report identifying specific mechanisms underlying acquired resistance to TNF could lead to a better understanding of the progression of breast cancer in response to chemotherapy treatment.


Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Drug Resistance, Neoplasm , Epithelial-Mesenchymal Transition/genetics , Receptors, Tumor Necrosis Factor/metabolism , Signal Transduction , Animals , Apoptosis , Cell Line, Tumor , Cell Survival/genetics , Cell Transformation, Neoplastic/genetics , Cluster Analysis , Disease Models, Animal , Estrogen Receptor alpha/metabolism , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Mice , Mice, Nude , NF-kappa B/metabolism , Receptors, Death Domain , Tumor Necrosis Factor-alpha/pharmacology , Tumor Necrosis Factor-alpha/toxicity , Xenograft Model Antitumor Assays
10.
J Endocrinol ; 214(1): 45-54, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22562654

ABSTRACT

The estrogen receptor α (ERα) is a transcription factor that mediates the biological effects of 17ß-estradiol (E(2)). ERα transcriptional activity is also regulated by cytoplasmic signaling cascades. Here, several Gα protein subunits were tested for their ability to regulate ERα activity. Reporter assays revealed that overexpression of a constitutively active Gα(o) protein subunit potentiated ERα activity in the absence and presence of E(2). Transient transfection of the human breast cancer cell line MCF-7 showed that Gα(o) augments the transcription of several ERα-regulated genes. Western blots of HEK293T cells transfected with ER±Gα(o) revealed that Gα(o) stimulated phosphorylation of ERK 1/2 and subsequently increased the phosphorylation of ERα on serine 118. In summary, our results show that Gα(o), through activation of the MAPK pathway, plays a role in the regulation of ERα activity.


Subject(s)
Estrogen Receptor alpha/metabolism , MAP Kinase Signaling System , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Blotting, Western , Cell Line, Tumor , Estradiol/pharmacology , Estrogen Receptor alpha/genetics , Extracellular Signal-Regulated MAP Kinases , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , Gene Expression Regulation/drug effects , HEK293 Cells , Humans , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 3/genetics , Mutation , Phosphorylation/drug effects , Reverse Transcriptase Polymerase Chain Reaction , Serine/genetics , Serine/metabolism , Transfection
11.
J Steroid Biochem Mol Biol ; 132(1-2): 186-93, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22634477

ABSTRACT

Flavonoid phytochemicals act as both agonists and antagonists of the human estrogen receptors (ERs). While a number of these compounds act by directly binding to the ER, certain phytochemicals, such as the flavonoid compounds chalcone and flavone, elicit antagonistic effects on estrogen signaling independent of direct receptor binding. Here we demonstrate both chalcone and flavone function as cell type-specific selective ER modulators. In MCF-7 breast carcinoma cells chalcone and flavone suppress ERα activity through stimulation of the stress-activated members of the mitogen-activated protein kinase (MAPK) family: c-Jun N-terminal kinase (JNK)1 and JNK2. The use of dominant-negative mutants of JNK1 or JNK2 in stable transfected cells established that the antiestrogenic effects of chalcone and flavone required intact JNK signaling. We further show that constitutive activation of the JNK pathway partially suppresses estrogen (E2)-mediated gene expression in breast, but not endometrial carcinoma cells. Our results demonstrate a role for stress-activated MAPKs in the cell type-specific regulation of ERα function.


Subject(s)
Chalcone/pharmacology , Estrogen Receptor Modulators/pharmacology , Estrogen Receptor alpha/metabolism , Flavones/pharmacology , JNK Mitogen-Activated Protein Kinases/metabolism , Cell Line, Tumor , Estradiol/pharmacology , HEK293 Cells , Humans
12.
Oncol Rep ; 27(6): 1779-86, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22469881

ABSTRACT

Recent research has demonstrated that aberrant sphingolipid signaling is an important mechanism of chemoresistance in solid tumors. Sphingosine kinase (Sphk), the primary enzyme metabolizing the sphingolipid ceramide into sphingosine-1-phosphate (S1P), is a primary mediator of breast cancer promotion, survival and chemoresistance. However, to date the mechanism of Sphk-mediated drug resistance is poorly understood. Using the dual sphingosine kinase isozyme inhibitor, SKI-II (4-[4-(4-chloro-phenyl)-thiazol-2-ylamino]-phenol), we explored the effects of sphingosine kinase inhibition on multi-drug-resistant breast cancer cells. We demonstrate that SKI-II alters endogenous sphingolipid signaling and decreases cancer proliferation, survival and viability. Furthermore, pharmacological inhibition of Sphk1/2 induced intrinsic apoptosis in these cells through modulation of the NF-κB pathway. SKI-II decreases NF-κB transcriptional activity through altered phosphorylation of the p65 subunit. Taken together, these results suggest that Sphk may be a promising therapeutic target in chemoresistant cancers.


Subject(s)
Breast Neoplasms/drug therapy , Drug Resistance, Neoplasm , NF-kappa B/metabolism , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Thiazoles/pharmacology , Tumor Necrosis Factor-alpha/metabolism , Apoptosis/drug effects , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Resistance, Multiple , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , NF-kappa B/genetics , Phosphorylation , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Signal Transduction/drug effects , Transcription Factor RelA/metabolism
13.
Bioorg Med Chem Lett ; 22(7): 2624-8, 2012 Apr 01.
Article in English | MEDLINE | ID: mdl-22366655

ABSTRACT

The ceramide-sphingosine-1-phosphate rheostat is a promising therapeutic target. Here, the novel ceramide analog (S)-2-(benzylideneamino)-3-hydroxy-N-tetrade-cylpropanamide is shown to block proliferation and enhance the efficacy of the clinical chemotherapeutics, etoposide and doxorubicin. These results demonstrate the therapeutic potential of this compound in treating both endocrine resistant and chemoresistant breast cancer.


Subject(s)
Antineoplastic Agents/chemical synthesis , Ceramides/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Ceramides/pharmacology , Doxorubicin/pharmacology , Drug Resistance, Neoplasm , Drug Synergism , Etoposide/pharmacology , Female , Humans , Ki-67 Antigen/biosynthesis , Lysophospholipids/metabolism , Sphingosine/analogs & derivatives , Sphingosine/metabolism , Stereoisomerism , Structure-Activity Relationship
14.
Cancer Invest ; 30(2): 135-48, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22250588

ABSTRACT

With an estimated 207,090 patients diagnosed with breast cancer in 2010, the role of chemotherapy-induced cognitive impairment is of growing importance. Studies to determine the impact of chemotherapy-induced cognitive impairment have been hindered by difficulties in study-design, in particular, study methodology. Here, we present a review of existing studies and discuss several mechanisms for chemotherapy-induced neurocognitive impairment in breast cancer patients, such as direct neurotoxic injury, telomere shortening, oxidative stress, cytokine dysregulation, estrogen-mediated effects, and the role of certain genetic polymorphisms. Decreased estrogen levels may serve as a link between multiple mechanisms potentiating the effects of the chemotherapy-induced cognitive impairment.


Subject(s)
Antineoplastic Agents/adverse effects , Breast Neoplasms/drug therapy , Cognition Disorders/chemically induced , Antineoplastic Agents/therapeutic use , Breast Neoplasms/psychology , Cognition Disorders/psychology , Female , Humans , Neuropsychological Tests , Prospective Studies
15.
Biochim Biophys Acta ; 1825(1): 37-48, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22020294

ABSTRACT

While conventional MAP kinase pathways are one of the most highly studied signal transduction molecules, less is known about the MEK5 signaling pathway. This pathway has been shown to play a role in normal cell growth cycles, survival and differentiation. The MEK5 pathway is also believed to mediate the effects of a number of oncogenes. MEK5 is the upstream activator of ERK5 in many epithelial cells. Activation of the MEK-MAPK pathway is a frequent event in malignant tumor formation and contributes to chemoresistance and anti-apoptotic signaling. This pathway may be involved in a number of more aggressive, metastatic varieties of cancer due to its role in cell survival, proliferation and EMT transitioning. Further study of this pathway may lead to new prognostic factors and new drug targets to combat more aggressive forms of cancer.


Subject(s)
MAP Kinase Kinase 5/metabolism , MAP Kinase Signaling System/physiology , Mitogen-Activated Protein Kinase 7/metabolism , Neoplasms/metabolism , Cell Differentiation , Cell Survival , Epithelial-Mesenchymal Transition , Humans , MAP Kinase Kinase 5/antagonists & inhibitors , Mitogen-Activated Protein Kinase 7/antagonists & inhibitors
17.
Cancer Biol Ther ; 11(7): 678-89, 2011 Apr 01.
Article in English | MEDLINE | ID: mdl-21307639

ABSTRACT

Resistance to chemotherapy remains a significant obstacle in the treatment of hormone- independent breast cancer. Recent evidence suggests that altered sphingolipid signaling through increased sphingosine kinase activity may be an important mediator of breast cancer drug resistance. Sphingosine kinase-1 (Sphk1) is a proposed key regulator of breast cancer tumorigenesis, proliferation and resistance. There is, however, conflicting data on the role of sphingosine kinase-2 (Sphk2) in cancer biology and resistance, with some suggesting that Sphk2 has an opposing role to that of Sphk1. Here, we studied the effects of the novel selective Sphk2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl) amide), on human breast cancer. ABC294640 blocked both viability and survival at low micromolar IC(50) concentrations in the endocrine therapy-resistant MDA-MB-231 and chemoresistant MCF-7TN-R cell systems. Treatment with the inhibitor significantly reduced proliferation, as seen in immunofluorescence staining of Ki-67 in vitro. Interestingly, pharmacological inhibition of Sphk2 induced apoptosis through the intrinsic programmed cell death pathway. Furthermore, ABC294640 also diminished NF-ĸB survival signaling, through decreased activation of the Ser536 phosphorylation site on the p65 subunit. Xenografts of MCF-7TN-R cells growing in immunocompromised mice were utilized to validate the therapeutic efficacy of the sphingosine kinase-2 inhibitor. Treatment with 50 mg of ABC294640/kg completely blocked tumor volume in this model. These results indicate that pharmacological inhibition of Sphk2 with the orally bioavailable selective inhibitor, ABC294640, has therapeutic potential in the treatment of chemo- and endocrine therapy- resistant breast cancer.


Subject(s)
Adamantane/analogs & derivatives , Antineoplastic Agents/pharmacology , Breast Neoplasms/enzymology , Drug Resistance, Neoplasm/genetics , Enzyme Inhibitors/pharmacology , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Pyridines/pharmacology , Adamantane/pharmacology , Animals , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Female , Humans , Mice , Mice, SCID , Molecular Targeted Therapy , Phosphotransferases (Alcohol Group Acceptor)/genetics , Receptors, Estrogen/metabolism , Signal Transduction/drug effects , Xenograft Model Antitumor Assays , NF-kappaB-Inducing Kinase
18.
J Mol Endocrinol ; 46(3): 205-16, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21321095

ABSTRACT

Recently, crosstalk between sphingolipid signaling pathways and steroid hormones has been illuminated as a possible therapeutic target. Sphingosine kinase (SK), the key enzyme metabolizing pro-apoptotic ceramide to pro-survival sphingosine-1-phosphate (S1P), is a promising therapeutic target for solid tumor cancers. In this study, we examined the ability of pharmacological inhibition of S1P formation to block estrogen signaling as a targeted breast cancer therapy. We found that the Sphk1/2 selective inhibitor (SK inhibitor (SKI))-II, blocked breast cancer viability, clonogenic survival and proliferation. Furthermore, SKI-II dose-dependently decreased estrogen-stimulated estrogen response element transcriptional activity and diminished mRNA levels of the estrogen receptor (ER)-regulated genes progesterone receptor and steroid derived factor-1. This inhibitor binds the ER directly in the antagonist ligand-binding domain. Taken together, our results suggest that SKIs have the ability to act as novel ER signaling inhibitors in breast carcinoma.


Subject(s)
Breast Neoplasms/metabolism , Isoenzymes/metabolism , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Signal Transduction/drug effects , Thiazoles/pharmacology , Blotting, Western , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Computer Simulation , Estrogen Receptor alpha , Humans , Isoenzymes/antagonists & inhibitors , Mass Spectrometry , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Reverse Transcriptase Polymerase Chain Reaction
19.
Cancer Res ; 71(2): 603-13, 2011 Jan 15.
Article in English | MEDLINE | ID: mdl-21123450

ABSTRACT

Estrogen independence and progression to a metastatic phenotype are hallmarks of therapeutic resistance and mortality in breast cancer patients. Metastasis has been associated with chemokine signaling through the SDF-1-CXCR4 axis. Thus, the development of estrogen independence and endocrine therapy resistance in breast cancer patients may be driven by SDF-1-CXCR4 signaling. Here we report that CXCR4 overexpression is indeed correlated with worse prognosis and decreased patient survival irrespective of the status of the estrogen receptor (ER). Constitutive activation of CXCR4 in poorly metastatic MCF-7 cells led to enhanced tumor growth and metastases that could be reversed by CXCR4 inhibition. CXCR4 overexpression in MCF-7 cells promoted estrogen independence in vivo, whereas exogenous SDF-1 treatment negated the inhibitory effects of treatment with the anti-estrogen ICI 182,780 on CXCR4-mediated tumor growth. The effects of CXCR4 overexpression were correlated with SDF-1-mediated activation of downstream signaling via ERK1/2 and p38 MAPK (mitogen activated protein kinase) and with an enhancement of ER-mediated gene expression. Together, these results show that enhanced CXCR4 signaling is sufficient to drive ER-positive breast cancers to a metastatic and endocrine therapy-resistant phenotype via increased MAPK signaling. Our findings highlight CXCR4 signaling as a rational therapeutic target for the treatment of ER-positive, estrogen-independent breast carcinomas needing improved clinical management.


Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Estradiol/analogs & derivatives , Receptors, CXCR4/biosynthesis , Animals , Breast Neoplasms/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm , Estradiol/pharmacology , Estrogen Antagonists/pharmacology , Female , Fulvestrant , Humans , MAP Kinase Signaling System , Mice , Mice, SCID , Neoplasm Metastasis , Neoplasms, Hormone-Dependent/metabolism , Neoplasms, Hormone-Dependent/pathology , Receptors, CXCR4/metabolism , Receptors, Estrogen/antagonists & inhibitors , Receptors, Estrogen/biosynthesis
20.
Mol Cancer ; 9: 295, 2010 Nov 18.
Article in English | MEDLINE | ID: mdl-21087507

ABSTRACT

BACKGROUND: Adult human mesenchymal stem cells (hMSC) have been shown to home to sites of carcinoma and affect biological processes, including tumour growth and metastasis. Previous findings have been conflicting and a clear understanding of the effects of hMSCs on cancer remains to be established. Therefore, we set out to investigate the impact of hMSCs on the oestrogen receptor positive, hormone-dependent breast carcinoma cell line MCF-7. RESULTS: In this study, we show the effects of hMSCs on cancer cells are mediated through a secreted factor(s) which are enhanced by cancer cell-hMSC contact/communication. In addition to enhanced proliferation when in co-culture with hMSCs, MCF-7 cells were found to have increased migration potential in vitro. Inhibition of ER signalling by the pure anti-oestrogen ICI 182,780 decreased the effect of hMSCs on MCF-7 cell proliferation and migration supporting a role for ER signalling in the hMSC/MCF-7 cell interaction. Additionally, hMSCs have been shown to secrete a wide variety of growth factors and chemokines including stromal cell-derived factor-1 (SDF-1). This coupled with the knowledge that SDF-1 is an ER-mediated gene linked with hormone-independence and metastasis led to the investigation of the SDF-1/CXCR4 signalling axis in hMSC-MCF-7 cell interaction. Experiments revealed an increase in SDF-1 gene expression both in vivo and in vitro when MCF-7 cells were cultured with hMSCs. SDF-1 treatment of MCF-7 cells alone increased proliferation to just below that seen with hMSC co-culture. Additionally, blocking SDF-1 signalling using a CXCR4-specific inhibitor decreased hMSC induced proliferation and migration of MCF-7. However, the combined treatment of ICI and AMD3100 reduced MCF-7 cell proliferation and migration below control levels, indicating targeting both the ER and CXCR4 pathways is effective in decreasing the hMSCs induction of MCF-7 cell proliferation and migration. CONCLUSIONS: The sum of these data reveals the relationship between tumour microenvironment and tumour growth and progression. Better understanding of the mechanisms involved in this tumour stroma cell interaction may provide novel targets for the development of treatment strategies for oestrogen receptor positive, hormone-independent, and endocrine-resistant breast carcinoma.


Subject(s)
Breast Neoplasms/metabolism , Carcinoma/metabolism , Chemokine CXCL12/metabolism , Mesenchymal Stem Cells/metabolism , Receptors, CXCR4/metabolism , Receptors, Estrogen/metabolism , Benzylamines , Breast Neoplasms/pathology , Cell Differentiation/genetics , Cell Differentiation/physiology , Cell Line, Tumor , Cell Movement/genetics , Cell Movement/physiology , Cell Proliferation/drug effects , Cells, Cultured , Chemokine CXCL12/genetics , Chemokine CXCL12/pharmacology , Coculture Techniques , Cyclams , Female , Flow Cytometry , Heterocyclic Compounds/pharmacology , Humans , Microscopy, Fluorescence , Receptors, CXCR4/antagonists & inhibitors , Receptors, Estrogen/antagonists & inhibitors , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects
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