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Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1-mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma.

ABSTRACT: BACKGROUND:Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Phloretin (PH) possesses anticancer, antitumor, and hepatoprotective effects, however, the effects and potential mechanisms of phloretin remain elusive. METHODS:Five HCC cells were tested in vitro for sensitivity to PH, Sorafenib (Sor) or both and the apoptosis, signal transduction and phosphatase activity were analyzed. To validate the role of SHP-1, we used PTP inhibitor III and SHP-1 siRNA. Further, we used purified SHP-1 proteins or HCC cells expressing deletion N-SH2 domain or D61A point mutants to study the PH efficacy on SHP-1. The `in vivo studies were conducted using HepG2 and SK-Hep1 and Sor resistant HepG2SR and Huh7SR xenografts. Molecular docking was done with Swiss dock and Auto Dock Vina. RESULTS:PH inhibited cell growth and induced apoptosis in all HCC cells by upregulating SHP-1 expression and downregulating STAT3 expression and further inhibited pAKT/pERK signaling. PH activated SHP-1 by disruption of autoinhibition of SHP-1, leading to reduced p-STAT3Tyr705 level. PH induced apoptosis in two Sor-resistant cell lines and overcome STAT3, AKT, MAPK and VEGFR2 dependent Sor resistance in HCCs. PH potently inhibited tumor growth in both Sor-sensitive and Sor-resistant xenografts in vivo by impairing angiogenesis, cell proliferation and inducing apoptosis via targeting the SHP-1/STAT3 signaling pathway. CONCLUSION:Our data suggest that PH inhibits STAT3 activity in Sor-sensitive and -resistant HCCs via SHP-1-mediated inhibition of STAT3 and AKT/mTOR/JAK2/VEGFR2 pathway. Our results clearly indicate that PH may be a potent reagent for hepatocellular carcinoma and a noveltargeted therapy for further clinical investigations.

SUBMITTER: Saraswati S

PROVIDER: S-EPMC6794763 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1-mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma.

Saraswati Sarita S Alhaider Abdulqader A Abdelgadir Abdelgalil Mohamed AM Tanwer Pooja P Korashy Hesham M HM

Cell communication and signaling : CCS 20191016 1

<h4>Background</h4>Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Phloretin (PH) possesses anticancer, antitumor, and hepatoprotective effects, however, the effects and potential mechanisms of phloretin remain elusive.<h4>Methods</h4>Five HCC cells were tested in vitro for sensitivity to PH, Sorafenib (Sor) or both and the apoptosis, signal transduction and phosphatase activity were analyzed. To validate the role of SHP-1, we used PTP inhibitor III and SHP-1 siRNA. F ...[more]

PMID: 31619257

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Project description:Simple Summary Hepatocellular cancer (HCC) is the most common and lethal subtype of liver cancer without effective therapeutics. Understanding and targeting cancer stem cells (CSCs), a stem-cell-like subpopulation, which are emerging as effective ways to decipher tumor biology and develop therapies, may help to revolutionize cancer management. Cancer/testis antigen Maelstrom (MAEL) has been implicated in the regulation of CSC phenotypes, while the role of CSCs remains unclear. We demonstrated that MAEL positively regulates cancer stem-cell-like properties in HCC, and MAEL silencing provokes tumor cells’ sensitivity to sorafenib. We further discovered that the MAEL-dependent stemness was operated via PGST2/IL8/AKT/STAT3 signaling. Collectively, our study suggests the MAEL/PGST2 axis as a potential therapeutic target against CSC and sorafenib resistance in HCC. Abstract Cancer stem cells (CSCs) are responsible for tumorigenesis, therapeutic resistance, and metastasis in hepatocellular cancer (HCC). Cancer/testis antigen Maelstrom (MAEL) is implicated in the formation of CSC phenotypes, while the exact role and underlying mechanism remain unclear. Here, we found the upregulation of MAEL in HCC, with its expression negatively correlated with survival outcome. Functionally, MAEL promoted tumor cell aggressiveness, tumor stem-like potentials, and resistance to sorafenib in HCC cell lines. Transcriptional profiling indicated the dysregulation of stemness in MAEL knockout cells and identified PTGS2 as a critical downstream target transactivated by MAEL. The suppression effect of MAEL knockout in tumor aggressiveness was rescued in PTGS2 overexpression HCC cells. A molecular mechanism study revealed that the upregulation of PTGS2 by MAEL subsequently resulted in IL-8 secretion and the activation of AKT/NF-κB/STAT3 signaling. Collectively, our work identifies MAEL as an important stemness regulation gene in HCC. Targeting MAEL or its downstream molecules may provide a novel possibility for the elimination of CSC to enhance therapeutic efficacy for HCC patients in the future.

Project description:BackgroundSorafenib is approved as a standard therapy for advanced hepatocellular carcinoma (HCC), but its clinical application is limited due to moderate therapeutic efficacy and high incidence of acquired resistance resulted from elevated levels of SDF-1/CXCR4 axis induced by prolonged sorafenib treatment. We previously demonstrated metapristone (RU486 metabolite) as a cancer metastatic chemopreventive agent targeting SDF-1/CXCR4 axis. Therefore, we hypothesized that combining sorafenib with metapristone could synergistically suppress cell proliferation, enhance anti-cancer activity and repress potential drug resistance.MethodsChanges in cellular CXCR4 expression by metapristone were analyzed by RT-PCR and western blotting. Effect of combining sorafenib with metapristone on cell viability was examined by MTT assay; combination index value was calculated to evaluate the synergistic effect of combined therapy. To overcome poor pharmacokinetics and reduce off-target toxicity, CXCR4-targeted nanoparticles (NPs) were developed to co-deliver sorafenib and metapristone into CXCR4-expressing HCC in vitro and in vivo; cell proliferation, colony formation and apoptosis assays were conducted; nude mice bearing HCC xenograft were used to examine effects of this therapeutic approach on HCC progression.ResultsHere we showed metapristone significantly reduced CXCR4 expression in HCC. Combinatory chemotherapy of sorafenib with metapristone synergistically suppressed HCC proliferation and resistance. CXCR4-targeted PEGylated poly (lactic-co-glycolic acid) NPs conjugated with LFC131 (a peptide inhibitor of CXCR4), could deliver more sorafenib and metapristone into HCC via specific recognition and binding with transmembrane CXCR4, and resulted in the enhanced cytotoxicity, colony inhibition and apoptosis by regulating more Akt/ERK/p38 MAPK/caspase signaling pathways. Co-delivery of sorafenib with metapristone by the LFC131-conjugated NPs showed prolonged circulation and target accumulation at tumor sites, and thus suppressed tumor growth in a tumor xenograft model.ConclusionsIn conclusion, co-delivery of sorafenib and metapristone via the CXCR4-targeted NPs displays a synergistic therapy against HCC. Our results suggest combinational treatment of chemotherapeutics offer an effective strategy for enhancing the therapeutic efficacy on carcinoma, and highlight the potential application of ligand-modified tumor-targeting nanocarriers in delivering drugs as a promising cancer therapeutic approach.

Dataset Information

Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1-mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma.

Publications

Phloretin attenuates STAT-3 activity and overcomes sorafenib resistance targeting SHP-1-mediated inhibition of STAT3 and Akt/VEGFR2 pathway in hepatocellular carcinoma.

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