Down-Regulation of TGF-β Expression Sensitizes the Resistance of Hepatocellular Carcinoma Cells to Sorafenib
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Purpose: Sorafenib, a multikinase inhibitor, is the standard therapy for patients with advanced-stage hepatocellular carcinoma (HCC). However, resistance develops to the treatment, therefore, we tried to unravel the underlying mechanism in the resistance of HCC cells to sorafenib via the development of more effective therapeutic strategies. Materials and Methods: Various liver cancer cell lines were treated with either sorafenib only or with sorafenib after infection of adenovirus expressing short hairpin RNA (shRNA) against transforming growth factor-β (TGF-β) and p38 activity was examined using western blotting. Results: p38 MAP kinase activity was inhibited by low concentrations of sorafenib, which could potentially lead to sorafenib resistancein HCC cell lines. Subsequently, we used constitutive form of MKK3/6 (MKK3/6E) to confirm that massive cell death was induced by the activation of p38, and demonstrated the ability to activate p38 without any stimulation. In addition, sorafenib resistancewas reduced by the activation of p38. Subsequently, we confirmed that TGF-β shRNA effectively recovered the phosphorylationof p38 inhibited by sorafenib, and increased the sensitivity of HCC cells to sorafenib, thereby inducing cell death and overcoming the resistance of HCC cells to sorafenib. Conclusion: Our study provides a new therapeutic strategy for HCC that overcomes the resistance of HCC to sorafenib by down-regulation of TGF-β
Abstract
Purpose: Sorafenib, a multikinase inhibitor, is the standard therapy for patients with advanced-stage hepatocellular carcinoma (HCC). However, resistance develops to the treatment, therefore, we tried to unravel the underlying mechanism in the resistance of HCC cells to sorafenib via the development of more effective therapeutic strategies. Materials and Methods: Various liver cancer cell lines were treated with either sorafenib only or with sorafenib after infection of adenovirus expressing short hairpin RNA (shRNA) against transforming growth factor-β (TGF-β) and p38 activity was examined using western blotting. Results: p38 MAP kinase activity was inhibited by low concentrations of sorafenib, which could potentially lead to sorafenib resistancein HCC cell lines. Subsequently, we used constitutive form of MKK3/6 (MKK3/6E) to confirm that massive cell death was induced by the activation of p38, and demonstrated the ability to activate p38 without any stimulation. In addition, sorafenib resistancewas reduced by the activation of p38. Subsequently, we confirmed that TGF-β shRNA effectively recovered the phosphorylationof p38 inhibited by sorafenib, and increased the sensitivity of HCC cells to sorafenib, thereby inducing cell death and overcoming the resistance of HCC cells to sorafenib. Conclusion: Our study provides a new therapeutic strategy for HCC that overcomes the resistance of HCC to sorafenib by down-regulation of TGF-β
참고문헌 (25)
- McGlynn KA, "The global epidemiology of hepatocellular carcinoma: present and future", Clin Liver Dis, 15, pp.223~243 (2011)
- Llovet JM, "Hepatocellular carcinoma", Lancet, 362, pp.1907~1917 (2003)
- Llovet JM, "Sorafenib in advanced hepatocellular carcinoma", N Engl J Med, 359, pp.378~390 (2008)
- Bruix J, "Management of hepatocellular carcinoma", Hepatology, 42, pp.1208~1236 (2005)
- Zhai B, "Inhibition of Akt reverses the acquired resistance to sorafenib by switching protective autophagy to autophagic cell death in hepatocellular carcinoma", Mol Cancer Ther, 13, pp.1589~1598 (2014)
- Wilhelm SM, "Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling", Mol Cancer Ther, 7, pp.3129~3140 (2008)
- Wilhelm SM, "BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF", MEK, Cancer Res, pp.2004, 64[DOI]
- Cheng AL, "Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial", Lancet Oncol, 10, pp.25~34 (2009)
- Zhai B, "Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma", World J Hepatol, 5, pp.345~352 (2013)
- Berasain C, "Hepatocellular carcinoma and sorafenib: too many resistance mechanisms?", Gut, 62, pp.1674~1675 (2013)
- Zhu YJ, "New knowledge of the mechanisms of sorafenib resistance in liver cancer", Acta Pharmacol Sin, 38, pp.614~622 (2017)
- Iyoda K, "Involvement of the p38 mitogen-activated protein kinase cascade in hepatocellular carcinoma", Cancer, 97, pp.3017~3026 (2003)
- Massagué J, "TGFbeta in cancer", Cell, 134, pp.215~230 (2008)
- Nagaraj NS, "Targeting the transforming growth factorbeta signaling pathway in human cancer", Expert Opin Investig Drugs, 19, pp.77~91 (2010)
- Papageorgis P, "TGFβ Signaling in Tumor Initiation, Epithelial-to-Mesenchymal Transition, and Metastasis", J Oncol, 2015, pp.587193~ (2015)
- Lin TH, "High serum transforming growth factor-β1 levels predict outcome in hepatocellular carcinoma patients treated with sorafenib", Clin Cancer Res, 21, pp.3678~3684 (2015)
- Dropmann A, "TGF-β1 and TGF-β2 abundance in liver diseases of mice and men", Oncotarget, 7, pp.19499~19518 (2016)
- Wilhelm S, "Discovery and development of sorafenib: a multikinase inhibitor for treating cancer", Nat Rev Drug Discov, 5, pp.835~844 (2006)
- Namboodiri HV, "Analysis of imatinib and sorafenib binding to p38alpha compared with c-Abl and b-Raf provides structural insights for understanding the selectivity of inhibitors targeting the DFG-out form of protein kinases", Biochemistry, 49, pp.3611~3618 (2010)
- Liu Y, "Rational design of inhibitors that bind to inactive kinase conformations", Nat Chem Biol, 2, pp.358~364 (2006)
- Grossi V, "Sorafenib inhibits p38α activity in colorectal cancer cells and synergizes with the DFG-in inhibitor SB202190 to increase apoptotic response", Cancer Biol Ther, 13, pp.1471~1481 (2012)
- Edelstein ML, "Gene therapy clinical trials worldwide to 2007--an update", J Gene Med, 9, pp.833~842 (2007)
- Adnane L, "Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF", MEK, PDGFR in tumor vasculature, pp.Methods Enzymol, 2006[DOI]
- Yang Y, "Molecular dynamics simulation and free energy calculation studies of the binding mechanism of allosteric inhibitors with p38α MAP kinase", J Chem Inf Model, 51, pp.3235~3246 (2011)
- Raingeaud J, "MKK3-and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway", Mol Cell Biol, 16, pp.1247~1255 (1996)