Synergistic interactions between sorafenib and bortezomib in hepatocellular carcinoma involve PP2A-dependent Akt inactivation

Chen, Kuen‐Feng; Yu, Huichuan; Liu, Tsung-Hao; Lee, Shoei‐Sheng; Chen, Pei‐Jer; Cheng, Ann‐Lii

doi:10.1016/j.jhep.2009.10.011

Cited by 66 publications

(51 citation statements)

References 28 publications

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“…Although phosphorylation of Akt can be induced by protein phosphatase inactivation (32), the present study showed that the sorafenib-induced Akt phosphorylation was independent of protein phosphatase 2A (PP2A), a major serine/threonine phosphatase in eukaryotic cells (33). In accord, the synergistic interaction between sorafenib and bortezomib, but not sorafenib alone, involved PP2A-dependent Akt inactivation in HCC cells (34). Akt regulates the expression and/or phosphorylation of mTOR, GSk3b, Bad and p27; mTOR regulates the apoptotic proteins S6K and 4EBP1, and the autophagic proteins LC3 and Beclin 1; and GSk3b regulates cyclin D1 and caspase-9 (refs.…”

Section: Discussionmentioning

confidence: 57%

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

Zhai

Jiang

et al. 2014

Molecular Cancer Therapeutics

241

234

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Sorafenib is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), but the acquired resistance to sorafenib results in limited benefits. Activation of Akt is thought to be responsible for mediating the acquired resistance to sorafenib. The present study aims to examine the underlying mechanism and seek potential strategies to reverse this resistance. Two sorafenib-resistant HCC cell lines, which had been established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition and apoptosis in vitro and in vivo. Sustained exposure to sorafenib activated Akt via the feedback loop of mTOR but independent of protein phosphatase 2A in HCC cells. Autophagy participated in the resistance to sorafenib as inhibition of autophagy reduced the sensitivity of sorafenib-resistant HCC cells to sorafenib, whereas activation of autophagy by rapamycin had the opposite effect. However, rapamycin did not show a synergistic effect with sorafenib to inhibit cell proliferation, while it also activated Akt via a feedback mechanism in sorafenib-resistant HCC cells. Inhibition of Akt reversed the acquired resistance to sorafenib by switching autophagy from a cytoprotective role to a death-promoting mechanism in the sorafenib-resistant HCC cells. Akt inhibition by GDC0068 synergized with sorafenib to suppress the growth of sorafenib-resistant HCC tumors that possessed the sorafenib-resistant feature in vivo. The results have provided evidence for clinical investigation of GDC0068, a novel ATP-competitive pan-Akt inhibitor, as the second-line treatment after the failure of sorafenib-medicated molecular targeted therapy for advanced HCC. Mol Cancer Ther; 13(6); 1589-98. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 57%

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

Zhai

Jiang

et al. 2014

Molecular Cancer Therapeutics

241

234

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“…Importantly, we found that protein phosphatase 2A (PP2A), a phosphatase which downregulates p-Akt, may mediate the effect of bortezomib on TRAIL sensitization (14). The mechanism by which bortezomib upregulates PP2A and, in turn, downregulates p-Akt was further delineated in our recent study on the synergistic interaction between bortezomib and sorafenib in HCC cells (18).…”

Section: Introductionmentioning

confidence: 71%

“…Our previous work showed that bortezomib increased PP2A activity in HCC cells (14,18). We, thus, next examined how bortezomib and CS-1008 combination treatment affected PP2A activity.…”

Section: Cip2a Inhibits Akt-associated Pp2a Activitymentioning

confidence: 98%

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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“…It has previously been reported that sorafenib plus bortezomib significantly suppressed PLC5 hepatocellular carcinoma cell xenograft tumor growth, downregulated p-Akt expression, and upregulated PP2A activity (24). Use of ceramide to treat PC-3 human prostate cancer cells revealed that ceramide-activated PP2A dephosphorylates phospho-Akt (25).…”

Section: Discussionmentioning

confidence: 98%

Zanthoxylum avicennae extracts inhibit cell proliferation through protein phosphatase 2A activation in HA22T human hepatocellular carcinoma cells in vitro and in vivo

et al. 2012

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Abstract. Hepatocellular carcinoma is a common type of cancer that is usually associated with poor prognosis. In this study, we examined the in vitro and in vivo mechanisms of the traditional Vietnamese herb Zanthoxylum avicennae on the inhibition of HA22T human hepatocellular carcinoma cell proliferation. HA22T cells were treated with different concentrations of Zanthoxylum avicennae extracts (YBBEs) and analyzed with the MTT assay, western blot analysis, flow cytometry, siRNA transfection assays and co-immunoprecipitation assay. Additionally, the HA22T-implanted xenograft nude mouse model was applied to confirm the cellular effects. YBBEs showed a strong inhibition of HA22T cell viability in a dose-dependent manner and significantly reduced cell proliferation-related proteins as well as induced cell cycle arrest in the G2/M phase. Protein phosphatase 2A (PP2A) siRNA or okadaic acid totally blocked YBBE-mediated cell proliferation inhibition. In addition, an HA22T-implanted nude mouse model further confirmed that YBBEs inhibit HA22T tumor cell growth and downregulate the survival and cell cycle regulating proteins, as well as activate the PP2A protein. Our findings indicate that the inhibition of HA22T cell proliferation by YBBEs is mediated through PP2A activation.

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Synergistic interactions between sorafenib and bortezomib in hepatocellular carcinoma involve PP2A-dependent Akt inactivation

Cited by 66 publications

References 28 publications

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

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

Zanthoxylum avicennae extracts inhibit cell proliferation through protein phosphatase 2A activation in HA22T human hepatocellular carcinoma cells in vitro and in vivo

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