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1.
Mol Oncol ; 11(8): 1035-1049, 2017 08.
Article in English | MEDLINE | ID: mdl-28453226

ABSTRACT

Palbociclib, a CDK4/6 inhibitor, has recently been approved for hormone receptor-positive breast cancer patients. The effects of palbociclib as a treatment for other malignancies, including hepatocellular carcinoma (HCC), are of great clinical interest and are under active investigation. Here, we report the effects and a novel mechanism of action of palbociclib in HCC. We found that palbociclib induced both autophagy and apoptosis in HCC cells through a mechanism involving 5' AMP-activated protein kinase (AMPK) activation and protein phosphatase 5 (PP5) inhibition. Blockade of AMPK signals or ectopic expression of PP5 counteracted the effect of palbociclib, confirming the involvement of the PP5/AMPK axis in palbociclib-mediated HCC cell death. However, CDK4/6 inhibition by lentivirus-mediated shRNA expression did not reproduce the effect of palbociclib-treated cells, suggesting that the anti-HCC effect of palbociclib is independent of CDK4/6. Moreover, two other CDK4/6 inhibitors (ribociclib and abemaciclib) had minimal effects on HCC cell viability and the PP5/AMPK axis. Palbociclib also demonstrated significant tumor-suppressive activity in a HCC xenograft model, which was associated with upregulation of pAMPK and PP5 inhibition. Finally, we analyzed 153 HCC clinical samples and found that PP5 expression was highly tumor specific and was associated with poor clinical features. Taken together, we conclude that palbociclib exerted antitumor activity against HCC through the PP5/AMPK axis independent of CDK4/6. Our findings provide a novel mechanistic basis for palbociclib and reveal the therapeutic potential of targeting PP5/AMPK signaling with a PP5 inhibitor for the treatment of hepatocellular carcinoma.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Carcinoma, Hepatocellular/metabolism , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/metabolism , Liver Neoplasms/metabolism , Neoplasm Proteins/metabolism , Piperazines/pharmacology , Pyridines/pharmacology , Signal Transduction/drug effects , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Enzyme Activation/drug effects , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology
3.
Sci Rep ; 6: 35308, 2016 10 18.
Article in English | MEDLINE | ID: mdl-27752061

ABSTRACT

Protein tyrosine phosphatase 1B (PTP1B) is known to promote the pathogenesis of diabetes and obesity by negatively regulating insulin and leptin pathways, but its role associated with colon carcinogenesis is still under debate. In this study, we demonstrated the oncogenic role of PTP1B in promoting colon carcinogenesis and predicting worse clinical outcomes in CRC patients. By co-immunoprecipitation, we showed that PITX1 was a novel substrate of PTP1B. Through direct dephosphorylation at Y160, Y175 and Y179, PTP1B destabilized PITX1, which resulted in downregulation of the PITX1/p120RasGAP axis. Interestingly, we found that regorafenib, the approved target agent for advanced CRC patients, exerted a novel property against PTP1B. By inhibiting PTP1B activity, regorafenib treatment augmented the stability of PITX1 protein and upregulated the expression of p120RasGAP in CRC. Importantly, we found that this PTP1B-dependant PITX1/p120RasGAP axis determines the in vitro anti-CRC effects of regorafenib. The above-mentioned effects of regorafenib were confirmed by the HT-29 xenograft tumor model. In conclusion, we demonstrated a novel oncogenic mechanism of PTP1B on affecting PITX1/p120RasGAP in CRC. Regorafenib inhibited CRC survival through reserving PTP1B-dependant PITX1/p120RasGAP downregulation. PTP1B may be a potential biomarker predicting regorafenib effectiveness, and a potential solution for CRC.


Subject(s)
Colorectal Neoplasms/drug therapy , Paired Box Transcription Factors/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics , p120 GTPase Activating Protein/genetics , Aged , Animals , Carcinogenesis/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic , HT29 Cells , Humans , Male , Mice , Middle Aged , Phenylurea Compounds/administration & dosage , Pyridines/administration & dosage , Xenograft Model Antitumor Assays
4.
Cancer Lett ; 371(2): 205-13, 2016 Feb 28.
Article in English | MEDLINE | ID: mdl-26679051

ABSTRACT

Sorafenib is the first and currently the only standard treatment for advanced hepatocellular carcinoma (HCC). We previously developed a sorafenib derivative SC-43, which exhibits much more enhanced anti-HCC activity than sorafenib and also promotes apoptosis in sorafenib-resistant HCC cells. Herein, a novel "sorafenib plus" combination therapy was developed by coupling sorafenib treatment with SC-43. Both sorafenib and SC-43 are proven Src homology region 2 domain containing phosphatase 1 (SHP-1) agonists. The combined actions of sorafenib and SC-43 enhanced SHP-1 activity, which was associated with diminished STAT3-related signals and stronger expression of apoptotic genes above that of either drug alone, culminating in increased cell death. Decreased p-STAT3 signaling and tumor size, as well as increased SHP-1 activity were observed in mice receiving the combination therapy in a subcutaneous HCC model. More reduced orthotopic HCC tumor size and prolonged survival were also observed in mice in the combination treatment arm compared to mice in either of the monotherapy arms. These results in the preclinical setting pave the way for further clinical studies to treat unresectable HCC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Hepatocellular/drug therapy , Enzyme Activators/pharmacology , Liver Neoplasms/drug therapy , Niacinamide/analogs & derivatives , Phenyl Ethers/pharmacology , Phenylurea Compounds/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Animals , Apoptosis/drug effects , Carcinoma, Hepatocellular/enzymology , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Synergism , Enzyme Activation , Humans , Liver Neoplasms/enzymology , Liver Neoplasms/pathology , Mice, Nude , Niacinamide/pharmacology , Phosphorylation , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Sorafenib , Time Factors , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
5.
J Agric Food Chem ; 62(44): 10768-75, 2014 Nov 05.
Article in English | MEDLINE | ID: mdl-25318692

ABSTRACT

Chemical components of lignocellulosic biomass may impede biofuel processing efficiency. To understand whether the heartwood of Acacia confusa is suitable for biofuel application, extractive-free heartwood of A. confusa was subjected to dilute acid (DA) or sulfite pretreatments. Sugar recoveries were used to evaluate the performance of different pretreatments. Cell wall properties, such as 4-O-alkylated lignin structures, S/G ratios, and xylan contents, of the pretreated samples showed significant correlations with the enzymatic saccharification of glucan. The 4% bisulfite-pretreated samples produced higher total sugar recoveries than DA-treated samples. The highest total sugar recoveries from DA and sulfite pretreatment were 52.0% (170 °C for 20 min) and 65.3% (4% NaHSO3 and 1% H2SO4), respectively. The results also demonstrated that the existence of extractives in the heartwood of A. confusa hindered the sugar recoveries from both the pretreatments and enzymatic saccharification. Total sugar recoveries were reduced 11.7-17.7% in heartwood samples with extractives.


Subject(s)
Acacia/chemistry , Biotechnology/methods , Wood/chemistry , Acids/chemistry , Biofuels/analysis , Hydrolysis , Sulfites/chemistry
6.
Proc Natl Acad Sci U S A ; 110(26): 10848-53, 2013 Jun 25.
Article in English | MEDLINE | ID: mdl-23754401

ABSTRACT

Laccases, as early as 1959, were proposed to catalyze the oxidative polymerization of monolignols. Genetic evidence in support of this hypothesis has been elusive due to functional redundancy of laccase genes. An Arabidopsis double mutant demonstrated the involvement of laccases in lignin biosynthesis. We previously identified a subset of laccase genes to be targets of a microRNA (miRNA) ptr-miR397a in Populus trichocarpa. To elucidate the roles of ptr-miR397a and its targets, we characterized the laccase gene family and identified 49 laccase gene models, of which 29 were predicted to be targets of ptr-miR397a. We overexpressed Ptr-MIR397a in transgenic P. trichocarpa. In each of all nine transgenic lines tested, 17 PtrLACs were down-regulated as analyzed by RNA-seq. Transgenic lines with severe reduction in the expression of these laccase genes resulted in an ∼40% decrease in the total laccase activity. Overexpression of Ptr-MIR397a in these transgenic lines also reduced lignin content, whereas levels of all monolignol biosynthetic gene transcripts remained unchanged. A hierarchical genetic regulatory network (GRN) built by a bottom-up graphic Gaussian model algorithm provides additional support for a role of ptr-miR397a as a negative regulator of laccases for lignin biosynthesis. Full transcriptome-based differential gene expression in the overexpressed transgenics and protein domain analyses implicate previously unidentified transcription factors and their targets in an extended hierarchical GRN including ptr-miR397a and laccases that coregulate lignin biosynthesis in wood formation. Ptr-miR397a, laccases, and other regulatory components of this network may provide additional strategies for genetic manipulation of lignin content.


Subject(s)
Down-Regulation/genetics , Laccase/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Populus/enzymology , Populus/genetics , RNA, Plant/genetics , RNA, Plant/metabolism , Base Sequence , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Plant , Gene Regulatory Networks , Genes, Plant , Laccase/antagonists & inhibitors , Lignin/antagonists & inhibitors , Lignin/chemistry , Lignin/metabolism , Phylogeny , Plant Proteins/genetics
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