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1.
Oncotarget ; 10(18): 1716-1728, 2019 Mar 01.
Article in English | MEDLINE | ID: mdl-30899443

ABSTRACT

The cholesterol-lowering statins have known anti-cancer effects, but the mechanisms and how to utilize statins in oncology have been unclear. We noted in the CellMiner database that statin activity against cancer lines correlated with higher expression of TGF-ß target genes such as SERPINE1 and ZYX. This prompted us to assess whether statins affected TGF-ß activity in glioblastoma (GBM), a cancer strongly influenced by TGF-ß and in dire need of new therapeutic approaches. We noted that statins reduced TGF-ß activity, cell viability and invasiveness, Rho/ROCK activity, phosphorylation and activity of the TGF-ß mediator Smad3, and expression of TGF-ß targets ZYX and SERPINE1 in GBM and GBM-initiating cell (GIC) lines. Statins were most potent against GBM, GIC, and other cancer cells with high TGF-ß activity, and exogenous TGF-ß further sensitized mesenchymal GICs to statins. Statin toxicity was rescued by addition of exogenous mevalonolactone or geranylgeranyl pyrophosphate, indicating that the observed effects reflected inhibition of HMG CoA-reductase by the statins. Simvastatin significantly inhibited the growth of subcutaneous GIC grafts and prolonged survival in GIC intracranially grafted mice. These results indicate where the statins might best be applied as adjunct therapies in oncology, against GBM and other cancers with high TGF-ß activity, and have implications for other statin roles outside of oncology.

2.
Cancer Res ; 78(15): 4360-4369, 2018 08 01.
Article in English | MEDLINE | ID: mdl-29844123

ABSTRACT

Glioblastoma (GBM) is the most common primary brain malignancy and carries an extremely poor prognosis. Recent molecular studies revealed the CDK4/6-Rb-E2F axis and receptor tyrosine kinase (RTK) signaling to be deregulated in most GBM, creating an opportunity to develop more effective therapies by targeting both pathways. Using a phospho-RTK protein array, we found that both c-Met and TrkA-B pathways were significantly activated upon CDK4/6 inhibition in GBM cells. We therefore investigated the efficacy of combined CDK4/6 and c-Met/TrkA-B inhibition against GBM. We show that both c-Met and TrkA-B pathways transactivate each other, and targeting both pathways simultaneously results in more efficient pathway suppression. Mechanistically, inhibition of CDK4/6 drove NF-κB-mediated upregulation of hepatocyte growth factor, brain-derived neurotrophic factor, and nerve growth factor that in turn activated both c-Met and TrkA-B pathways. Combining the CDK4/6 inhibitor abemaciclib with the c-Met/Trk inhibitor altiratinib or the corresponding siRNAs induced apoptosis, leading to significant synergy against GBM. Collectively, these findings demonstrate that the activation of c-Met/TrkA-B pathways is a novel mechanism involved in therapeutic resistance of GBM to CDK4/6 inhibition and that dual inhibition of c-Met/Trk with CDK4/6 should be considered in future clinical trials.Significance: CDK4/6 inhibition in glioblastoma activates the c-Met and TrkA-B pathways mediated by NF-κB and can be reversed by a dual c-Met/Trk inhibitor. Cancer Res; 78(15); 4360-9. ©2018 AACR.


Subject(s)
Brain Neoplasms/metabolism , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/metabolism , Glioblastoma/metabolism , Proto-Oncogene Proteins c-met/metabolism , Receptor, trkA/metabolism , Animals , Apoptosis/drug effects , Brain Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Glioblastoma/diet therapy , Humans , Mice , Mice, Inbred BALB C , Mice, SCID , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effects
3.
Neuro Oncol ; 20(2): 192-202, 2018 01 22.
Article in English | MEDLINE | ID: mdl-29048560

ABSTRACT

Background: The mesenchymal phenotype in glioblastoma (GBM) and other cancers drives aggressiveness and treatment resistance, leading to therapeutic failure and recurrence of disease. Currently, there is no successful treatment option available against the mesenchymal phenotype. Methods: We classified patient-derived GBM stem cell lines into 3 subtypes: proneural, mesenchymal, and other/classical. Each subtype's response to the inhibition of diacylglycerol kinase alpha (DGKα) was compared both in vitro and in vivo. RhoA activation, liposome binding, immunoblot, and kinase assays were utilized to elucidate the novel link between DGKα and geranylgeranyltransferase I (GGTase I). Results: Here we show that inhibition of DGKα with a small-molecule inhibitor, ritanserin, or RNA interference preferentially targets the mesenchymal subtype of GBM. We show that the mesenchymal phenotype creates the sensitivity to DGKα inhibition; shifting GBM cells from the proneural to the mesenchymal subtype increases ritanserin activity, with similar effects in epithelial-mesenchymal transition models of lung and pancreatic carcinoma. This enhanced sensitivity of mesenchymal cancer cells to ritanserin is through inhibition of GGTase I and downstream mediators previously associated with the mesenchymal cancer phenotype, including RhoA and nuclear factor-kappaB. DGKα inhibition is synergistic with both radiation and imatinib, a drug preferentially affecting proneural GBM. Conclusions: Our findings demonstrate that a DGKα-GGTase I pathway can be targeted to combat the treatment-resistant mesenchymal cancer phenotype. Combining therapies with greater activity against each GBM subtype may represent a viable therapeutic option against GBM.


Subject(s)
Brain Neoplasms/drug therapy , Diacylglycerol Kinase/antagonists & inhibitors , Glioblastoma/pathology , Ritanserin/pharmacology , Animals , Brain Neoplasms/pathology , Cell Line, Tumor , Diacylglycerol Kinase/genetics , Female , Humans , Mice, Inbred BALB C , NF-kappa B/metabolism , Signal Transduction/drug effects
4.
Clin Cancer Res ; 23(22): 6958-6968, 2017 Nov 15.
Article in English | MEDLINE | ID: mdl-28814434

ABSTRACT

Purpose: Glioblastoma (GBM) is a deadly brain tumor marked by dysregulated signaling and aberrant cell-cycle control. Molecular analyses have identified that the CDK4/6-Rb-E2F axis is dysregulated in about 80% of GBMs. Single-agent CDK4/6 inhibitors have failed to provide durable responses in GBM, suggesting a need to combine them with other agents. We investigate the efficacy of the combination of CDK4/6 inhibition and mTOR inhibition against GBM.Experimental Design: Preclinical in vitro and in vivo assays using primary GBM cell lines were performed.Results: We show that the CDK4/6 inhibitor palbociclib suppresses the activity of downstream mediators of the mTOR pathway, leading to rebound mTOR activation that can be blocked by the mTOR inhibitor everolimus. We further show that mTOR inhibition with everolimus leads to activation of the Ras mediator Erk that is reversible with palbociclib. The combined treatment strongly disrupts GBM metabolism, resulting in significant apoptosis. Further increasing the utility of the combination for brain cancers, everolimus significantly increases the brain concentration of palbociclib.Conclusions: Our findings demonstrate that the combination of CDK4/6 and mTOR inhibition has therapeutic potential against GBM and suggest it should be evaluated in a clinical trial. Clin Cancer Res; 23(22); 6958-68. ©2017 AACR.


Subject(s)
Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Glioblastoma/metabolism , Glioblastoma/pathology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Caspase 3/metabolism , Caspase 7/metabolism , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Disease Progression , Drug Synergism , Everolimus/pharmacology , Female , Glioblastoma/drug therapy , Humans , Mice , Models, Biological , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
5.
FEBS Lett ; 589(20 Pt B): 3090-7, 2015 Oct 07.
Article in English | MEDLINE | ID: mdl-26341534

ABSTRACT

The Drosophila Air Sac Primordium (ASP) has emerged as an important structure where cellular, genetic and molecular events responsible for invasive behavior and branching morphogenesis can be studied. In this report we present data which demonstrate that a Cathepsin-L encoded by the gene CP1 in Drosophila is necessary for invasive behavior during ASP development. We find that CP1 is expressed in ASP and knockdown of CP1 results in suppression of migratory and invasive behavior observed during ASP development. We further show that CP1 possibly regulates invasive behavior by promoting degradation of Basement Membrane. Our data provide clues to the possible role of Cathepsin L in human lung development and tumor invasion, especially, given the similarities between human lung and Drosophila ASP development.


Subject(s)
Air Sacs/metabolism , Cysteine Endopeptidases/metabolism , Drosophila Proteins/metabolism , Drosophila melanogaster/metabolism , Air Sacs/cytology , Air Sacs/growth & development , Animals , Animals, Genetically Modified , Basement Membrane/growth & development , Basement Membrane/metabolism , Cell Adhesion/genetics , Cell Movement/genetics , Cysteine Endopeptidases/genetics , Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Drosophila melanogaster/growth & development , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Humans , Larva/cytology , Larva/growth & development , Larva/metabolism , Microscopy, Confocal , Microscopy, Electron, Scanning , RNA Interference
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