Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis

Shi, Ying; Ding, Zheng; Zhou, Jian; Hui, Bo; Shi, Guo Hai; Ke, Ai–Wu; Wang, Xiaoying; Dai, Zhi; Yuan, Peng; Gu, Cheng Yu; Qiu, Shuang; Fan, Jian‐Gao

doi:10.4161/auto.7.10.16818

Cited by 293 publications

(284 citation statements)

References 32 publications

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“…However, the authors used a high concentration of sorafenib at 20 mmol/L (18). Even with the same concentration of sorafenib, another study showed that autophagy protected against sorafenib-induced cell death (20). Here, we have demonstrated that sorafenib at 10 mmol/L activated autophagy, which played a protective role against cell death of parental HCC cells, and is in agreement with a previous report (21); but exhibited a death-promoting role in sorafenib-resistant HCC cells.…”

Section: Discussionsupporting

confidence: 81%

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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: Discussionsupporting

confidence: 81%

“…Activation of autophagy is involved in the resistance to cisplatin (19), whereas inhibition of autophagy enhances the effect of sorafenib (20,21) in HCC cells. However, the role of autophagy and its cross-talk with other pathways in mediating resistance to sorafenib of HCC have not yet been reported.…”

Section: Introductionmentioning

confidence: 99%

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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“…In addition to the above described mechanisms, some limited studies have also demonstrated that EGFR [10] , glucose-regulated protein 78 (GRP78) [41] , multidrug resistance protein (MDRP) 2 [42] , nuclear factor κB (NF-κB) [43,44] and autophagy [45] may be involved in the acquired resistance to sorafenib in HCC.…”

Section: Hypoxic Microenvironment and Sorafenib Resistancementioning

confidence: 99%

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Zhai

Sun²

2013

WJH

163

152

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Sorafenib, the unique drug as first-line treatment for advanced hepatocellular carcinoma (HCC), has opened a window of hope after searching for effective agents to combat HCC for decades. However, the overall outcomes are far from satisfactory. One of the explanations is the genetic heterogeneity of HCC, which has led to identifying predictive biomarkers for primary resistance to sorafenib, and then applying the concept of personalized medicine, or seeking therapeutic strategies such as combining sorafenib with other anticancer agents. Some of the combinations have demonstrated a better effectiveness than sorafenib alone, with good tolerance. The acquired resistance to sorafenib has also drawn attention. As a multikinase inhibitor, sorafenib targets several cellular signaling pathways but simultaneously or sequentially the addiction switches and compensatory pathways are activated. Several mechanisms are involved in the acquired resistance to sorafenib, such as crosstalks involving PI3K/Akt and JAK-STAT pathways, hypoxia-inducible pathways, epithelial-mesenchymal transition, etc . Based on the investigated mechanisms, some other molecular targeted drugs have been applied as second-line treatment for treat HCC after the failure of sorafenib therapy and more are under evaluation in clinical trials. However, the exact mechanisms accounting for sorafenib resistance remains unclear. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms and help to find effective strategies for overcoming sorafenib resistance in HCC. Core tip: The primary resistance of hepatocellular carcinoma (HCC) to sorafenib is due to genetic heterogeneity. Thus, seeking predictive biomarkers and combining sorafenib with other anticancer agents for HCC have been launched with varying degrees of success. Sorafenib inhibits several kinase targets but it can also simultaneously or sequentially activate the addiction switches and compensatory pathways, inducing acquired resistance. Some other molecular targeted drugs have been used as second-line treatment for advanced HCC after the failure of sorafenib therapy. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms accounting for sorafenib resistance in HCC.Zhai B, Sun XY. Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma. World J Hepatol 2013; 5(7): 345-352 Available from:

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“…13 Our results showed that SLC9A3R1 augmented LC3 foci in MDA-MB-231 cells (Fig. 1B and C), and the knockdown of SLC9A3R1 inhibited the starvation-induced increase in LC3 foci in MCF-7 cells (Fig.…”

Section: Slc9a3r1 Stimulates Autophagy In Breast Cancer Cellsmentioning

confidence: 80%

“…As described previously, 13 breast cancer cells were immediately fixed with 2.5% glutaraldehyde containing 0.1 mol/L sodium cacodylate and stored at 4 C. The samples were then embedded, and ultrathin (50 to 60 nm) sections were cut using an ultramicrotome (LEICA EM UC7, Wetzlar, Germany). The samples were examined with a JEM-1400 electron microscope (JEOL USA, Inc., Peabody, MA) at 80 kV, and the images were captured with a Veleta TEM camera (Olympus, Shinjuku, Japan).…”

Section: Electron Microscopymentioning

confidence: 99%

SLC9A3R1 stimulates autophagy via BECN1 stabilization in breast cancer cells

Liu

et al. 2015

Autophagy

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Abbreviations: BCL2, B-cell CLL/lymphoma 2; CHX, cycloheximide; CQ, chloroquine; EGFR, epidermal growth factor receptor; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MTOR, mechanistic target of rapamycin (serine/threonine kinase); PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PIK3C3, phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4, phosphoinositide-3-kinase regulatory subunit 4; PTEN, phosphatase and tensin homolog; SLC9A3R1, solute carrier family 9, subfamily A (NHE3, cation proton antiporter 3), member 3 regulator 1; UB, ubiquitin.Autophagy, a self-catabolic process, has been found to be involved in abrogating the proliferation and metastasis of breast cancer. SLC9A3R1 (solute carrier family 9, subfamily A [NHE3, cation proton antiporter 3], member 3 regulator 1), a multifunctional scaffold protein, is involved in suppressing breast cancer cells proliferation and the SLC9A3R1-related signaling pathway regulates the activation of autophagy processes. However, the precise regulatory mechanism and signaling pathway of SLC9A3R1 in the regulation of autophagy processes in breast cancer cells remains unknown. Here, we report that the stability of BECN1, the major component of the autophagic core lipid kinase complex, is augmented in SLC9A3R1-overexpressing breast cancer MDA-MB-231 cells, subsequently stimulating autophagy by attenuating the interaction between BECN1 and BCL2. Initially, we found that SLC9A3R1 partially stimulated autophagy through the PTEN-PI3K-AKT1 signaling cascade in MDA-MB-231 cells. SLC9A3R1 then attenuated the interaction between BECN1 and BCL2 to stimulate the autophagic core lipid kinase complex. Further findings revealed that SLC9A3R1 bound to BECN1 and subsequently blocked ubiquitin-dependent BECN1 degradation. And the deletion of the C-terminal domain of SLC9A3R1 resulted in significantly reduced binding to BECN1. Moreover, the lack of C-terminal of SLC9A3R1 neither reduced the ubiquitination of BECN1 nor induced autophagy in breast cancer cells. The decrease in BECN1 degradation induced by SLC9A3R1 resulted in the activity of autophagy stimulation in breast cancer cells. These findings indicate that the SLC9A3R1-BECN1 signaling pathway participates in the activation of autophagy processes in breast cancer cells.

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Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stress-related apoptosis

Abstract: Fan (2011) Targeting autophagy enhances sorafenib lethality for hepatocellular carcinoma via ER stressrelated apoptosis,

Cited by 293 publications

References 32 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

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

SLC9A3R1 stimulates autophagy via BECN1 stabilization in breast cancer cells

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