Down-regulation of Phospho-Akt Is a Major Molecular Determinant of Bortezomib-Induced Apoptosis in Hepatocellular Carcinoma Cells

Chen, Kuen‐Feng; Yeh, Pei-Yen; Yeh, Kun‐Huei; Lu, Yen‐Shen; Huang, Shang-Yi; Cheng, Ann‐Lii

doi:10.1158/0008-5472.can-08-0257

Cited by 111 publications

(125 citation statements)

References 44 publications

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“…85,86 Recently, AKT signalling has been reported to be important for the enhanced BZ-induced apoptosis in HCC cells, through the inhibition of PI3K/ AKT pathway reports. [87][88][89] Despite the efficacy of BZ reports have also demonstrated that non-myeloma and myeloma cell lines can adapt and become resistant to to BZ-induced cell death. 90,91 The adaptation of the cells to BZ is partially due to changes, in the proteasome Figure 3.…”

Section: Atf4 and Autophagymentioning

confidence: 99%

Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia

Rzymski¹,

Milani²,

Singleton³

et al. 2009

Cell Cycle

171

130

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Section: Atf4 and Autophagymentioning

confidence: 99%

Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia

Rzymski¹,

Milani²,

Singleton³

et al. 2009

Cell Cycle

171

130

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“…The fact that multiple cellular targets are affected by bortezomib suggests its potential advantage in enhancing antitumor activities in combination treatment with TRAIL in HCC. Indeed, in our previous study, exploring the antitumor activity of bortezomib against HCC cells (17), we showed that downregulation of p-Akt determines the sensitivity of bortezomib, and that bortezomib-induced apoptosis may not be associated with proteasome inhibition in HCC cells. Moreover, we confirmed that bortezomib sensitized HCC cells to TRAIL through inhibition of p-Akt (14).…”

Section: Introductionmentioning

confidence: 96%

Bortezomib Sensitizes HCC Cells to CS-1008, an Antihuman Death Receptor 5 Antibody, through the Inhibition of CIP2A

Chen

Liu

et al. 2011

Molecular Cancer Therapeutics

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Previously, we have shown that bortezomib overcame TRAIL resistance in hepatocellular carcinoma (HCC) cells via the inhibition of Akt. Here, we report that bortezomib sensitizes these TRAIL-resistant cells, including Huh-7, Hep3B, and Sk-Hep1, to CS-1008, a humanized agonistic antihuman death receptor 5 antibody. Cancerous inhibitor of protein phosphatase 2A (CIP2A) mediated the sensitizing effect of bortezomib to CS-1008 through inhibiting protein phosphatase 2A (PP2A) activity. Combination treatment of bortezomib and CS-1008 downregulated CIP2A in a concentration-and time-dependent manner, and increased PP2A activity in HCC cells. Importantly, ectopic expression of CIP2A decreased Akt-related PP2A activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells. Moreover, silencing CIP2A by short interfering RNA enhanced CS-1008-induced apoptosis in HCC cells and ectopic expression of CIP2A in HCC cells abolished CS-1008-induced apoptosis, indicating that CIP2A plays an important role in the sensitizing effect of bortezomib to CS-1008. Finally, our in vivo data showed that CS-1008 and bortezomib combination treatment decreased tumor growth significantly. In conclusion, bortezomib sensitized HCC cells to CS-1008 through the inhibition of CIP2A. Mol Cancer Ther; 10(5); 892-901. Ó2011 AACR.

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“…(2) Substantial evidence from epidemiological studies indicates that HCC is strongly associated with alcohol abuse, chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), and liver cirrhosis. (3)(4)(5) More than one million people die of liver cancer worldwide every year. (6) Few patients are diagnosed in the early stage, and <20% of HCCs can be resected completely.…”

mentioning

confidence: 99%

MARVELD1 inhibited cell proliferation and enhance chemosensitivity via increasing expression of p53 and p16 in hepatocellular carcinoma

Zhang

et al. 2012

Cancer Science

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We have previously found that expression of MARVELD1 was remarkably downregulated in multiple tumor tissues, but unclear in hepatocellular carcinoma (HCC) and its function has not been explored yet. In the present study, to uncover the underlying mechanism of MARVELD1 in the pathogenesis and development of HCC, we investigated the expression pattern of MARVELD1 and its effect on tumor proliferation in HCC. The results indicated the frequent downregulation of MARVELD1 in clinic samples and cell lines of HCC resulted from promoter methylation, as well as genetic deletion. Furthermore, treatment of MARVELD1 unexpressing Hep3B2.1-7 and PLC/PRF/5 cells with the demethylating agent 5-aza-2′ deoxycytidine restored its expression. Overexpression of MARVELD1 suppressed the proliferation of HCC cells in vitro and in vivo, whereas downregulation of endogenous MARVELD1 by shRNAs significantly enhanced these characters. MARVELD1 overexpression could enhance chemosensitivity of HCC cells to epirubicin and 10-hydroxycamptothecin. Corresponding to these results, the expression of p-ERK1/2 and cyclin D1 were decreased, whereas p16 and p53 were increased in MAR-VELD1-transfected cells. We also demonstrated that knockdown of MARVELD1 resulted in upregulation of p-ERK1/2 and cyclin D1, and downregulation of p16 and p53. Moreover, the effect of the decreased cell growth rate was significantly reversed when MAR-VELD1-overexpressing cells were trasfected with p53 or p16 siR-NA. Our findings suggest that MARVELD1 is a tumor suppressor by negatively regulating proliferation, tumor growth and chemosensitivity of HCC cells via increasing p53 and p16 in vitro and in vivo. MARVELD1 may be a potential target for HCC therapy. (Cancer Sci 2012; 103: 716-722) H epatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, and its incidence is still rising.(1) Currently there are about 600 000 cases of HCC each year, and nearly 78% of them are from Asian countries.(2) Substantial evidence from epidemiological studies indicates that HCC is strongly associated with alcohol abuse, chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), and liver cirrhosis.(3-5) More than one million people die of liver cancer worldwide every year.(6) Few patients are diagnosed in the early stage, and <20% of HCCs can be resected completely. (7,8) Resistance to many of chemotherapy agents is a major obstacle to successful HCC treatment.(9-11) Therefore, a better understanding of the molecular mechanisms underlying HCC progression is urgently needed for leading to a more effective treatment.Genetic and epigenetic aberrations, leading to the activation of oncogenes and inactivation of tumor suppressor genes, are thought to play major roles in the pathogenesis of HCC. Recently, several MARVEL (proteins of the myelin and lymphocytes [MAL] and related proteins for vesicle trafficking and membrane link) domain-containing proteins have attracted increasing interest because they exhibit tumor suppressor activities a...

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Down-regulation of Phospho-Akt Is a Major Molecular Determinant of Bortezomib-Induced Apoptosis in Hepatocellular Carcinoma Cells

Cited by 111 publications

References 44 publications

Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia

Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia

Bortezomib Sensitizes HCC Cells to CS-1008, an Antihuman Death Receptor 5 Antibody, through the Inhibition of CIP2A

MARVELD1 inhibited cell proliferation and enhance chemosensitivity via increasing expression of p53 and p16 in hepatocellular carcinoma

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