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

Zhai, Bo; Hu, Fengli; Jiang, Xian; Xu, Jun; Zhao, Dan; Liu, Bing; Pan, Shangha; Dong, Xuesong; Tan, Gang; Wei, Zheng; Qiao, Haiquan; Jiang, Hongchi; Sun, Xueying

doi:10.1158/1535-7163.mct-13-1043

Cited by 238 publications

(247 citation statements)

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“…Additionally, previous studies revealed that stress activates the Akt signal transduction pathway in tumor cells, which results in protective autophagy (28). Furthermore, treatment with an Akt inhibitor changed the role of autophagy from protective to lethal (27). These findings suggest that Akt signaling and autophagy are important in the resistance of tumors to treatment.…”

Section: E C D B Amentioning

confidence: 77%

“…Akt may be the main mechanism of autophagic cell death, since the ectopic overexpression of Akt partly rescues cancer cells from death when they are stressed (8). Additionally, previous studies have demonstrated that stress activated the Akt signal transduction pathway in tumor cells and induced protective autophagy, whereas the inhibition of the Akt signaling pathway synergistically killed cancer cells (27). In the present study, the addition of ubenimex or an Akt inhibitor significantly induced autophagic cell death, whereas an Akt agonist reduced this effect.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, stress appears to activate the Akt signal transduction pathway in tumor cells, which results in protective autophagy (8,27). Therefore, to determine the involvement of the Akt signaling pathway in the effect of the above combined treatment, the levels of protein phosphorylation were detected by western blotting (Fig.…”

Section: Akt Signaling Pathway Is Involved In the Effect Of The Combimentioning

confidence: 99%

“…In addition, an Akt inhibitor could cause a switch from protective autophagy to autophagic cell death. This switch enhanced sorafenib resistance and cell proliferation in RCC cells (8,26,27). However, similar studies on RCC radiotherapy are rare.…”

Section: Introductionmentioning

confidence: 98%

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Ubenimex enhances the radiosensitivity of renal cell carcinoma cells by inducing autophagic cell death

et al. 2016

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Abstract. Renal cell carcinoma (RCC) is resistant to standard radiotherapy. Ubenimex, an aminopeptidase N inhibitor, is widely used as an adjunct therapy after surgery to enhance the function of immunocompetent cells and confer antitumor effects. Our previous study demonstrated that ubenimex induces autophagic cell death in RCC cells. Recently, the molecular mechanism of autophagy induction has been associated with radiosensitivity in RCC cells. In the present study, the ability of ubenimex to enhance RCC cell sensitivity to radiation via the induction of autophagic cell death was determined, and the mechanism of action of this effect was investigated. The 786-O and OS-RC-2 human RCC cell lines were treated with 0.5 mg/ml ubenimex and different doses of irradiation (IR). The cell viability was measured using a colony-formation assay and flow cytometry. Acridine orange (AO)-ethidium bromide (EB) staining was assessed by fluorescence microscopy as an indicator of autophagic cell death. Protein expression was assessed by western blotting. Autophagosomes were evaluated using transmission electron microscopy. RCC cells were used to evaluate the sensitivity to radiation using clonogenic survival and lactate dehydrogenase assays. Furthermore, these parameters were also tested at physiological oxygen levels.

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Section: E C D B Amentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Akt Signaling Pathway Is Involved In the Effect Of The Combimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Ubenimex enhances the radiosensitivity of renal cell carcinoma cells by inducing autophagic cell death

et al. 2016

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“…An immunoblotting assay was performed as previously described (16,17). Briefly, the cells were lysed and protein concentrations were quantified.…”

Section: Reverse Transcription-quantitative Pcr (Rt-qpcr)mentioning

confidence: 99%

Depletion of histone deacetylase 1 inhibits metastatic abilities of gastric cancer cells by regulating the miR-34a/CD44 pathway

et al. 2015

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Abstract. Overexpression of histone deacetylases (HDACs) is associated with higher metastatic rates and a poor prognosis in gastric cancer. However, the underlying mechanisms involved remain unclear. The present study aimed to investigate the molecular pathways that are involved in HDAC1-mediated metastatic activities in gastric cancer cells. First we used a microRNA (miRNA or miR) microarray to screen potential miRNAs whose expression can be altered by HDAC1 depletion. Of these miRNAs, miR-34a is important as it is often inactivated in cancer cells and acts as a tumor suppressor for various types of cancer. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results confirmed that miR-34a was upregulated by HDAC1 knockdown. Cells depleted of HDAC1 had lower abilities to migrate, invade and adhere, which were restored by a miR-34a antagomiR. Depletion of HDAC1 also resulted in impaired microfilaments and microtubules, while co-transfection of the miR-34a antagomiR attenuated these changes in the cellular cytoskeleton. The HDAC1/miR-34a axis regulated the expression and activation of CD44 and its downstream factors including Bcl-2, Ras homolog family member A (RhoA), LIM domain kinase 1 (LIMK-1) and matrix metalloproteinase (MMP)-2. The latter three proteins were responsible for the organization of tubulin and actin cytoskeleton and the formation of cellular pseudopodia. In conclusion, results of the present study indicated that HDAC1 depletion inhibits the metastatic abilities of gastric cancer cells by regulating the miRNA-34a/CD44 pathway, which may be a potential target for the treatment of gastric cancer. IntroductionGastric cancer remains the fourth most common malignancy and the second leading cause of cancer-related mortality worldwide, although its incidence is gradually on the decrease in most parts of the world (1). The currently available chemotherapeutic agents have only limited benefits for most gastric cancer patients. Therefore, identification of novel targets and an understanding of their molecular mechanisms is crucial for the treatment of gastric cancer patients.Histone deacetylases (HDACs) are a class of enzymes that remove the acetyl groups from core histones, as well as non-histone proteins, such as p53 (2). By modifying the status of deacetylation, HDACs induce transcriptional repression through chromatin condensation and alteration of protein activity (3). Among the 18 HDAC family members, HDAC1 accounts for more than half of cellular HDAC activity, and cannot be compensated by other HDACs (4). HDAC1 acts at all levels of gene expression including microRNA (miRNA or miR) regulation (5). Overexpression of HDAC1 is significantly associated with higher lymphatic metastases and decreased 3-year survival rates in gastric cancer patients (6). Many HDAC inhibitors have been developed, several of which have shown promise and are under investigation in clinical trials (3,7). However, the underlying mechanisms for the anti-metastatic activities of HDAC inhibitors, particularly...

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Dual inhibition of Akt and c‐Met as a second‐line therapy following acquired resistance to sorafenib in hepatocellular carcinoma cells

Han

Jiang

et al. 2017

Molecular Oncology

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Sorafenib displays a limited efficacy for advanced hepatocellular carcinoma (HCC). Some patients with HCC initially respond to sorafenib, but eventually succumb to the disease, indicating that the acquired resistance to sorafenib reduces its beneficial effects. No alternative drugs are available after the failure of sorafenib therapy. Therefore, investigation of the mechanisms underlying the acquired resistance and development of second‐line treatments for sorafenib‐resistant HCC are urgently required. In this study, sorafenib‐resistant HCC cells generated from sorafenib‐sensitive human HCC cells were shown to overproduce hepatocyte growth factor (HGF) and overexpress c‐Met kinase and its phosphorylated form, leading to the activation of Akt and ERK (extracellular signaling‐regulated kinase) pathways. Use of specific c‐Met inhibitors enhanced the effects of sorafenib by inhibiting the growth of sorafenib‐resistant HCC cells. Akt inhibitors, a class of second‐line therapeutic drugs under investigation for treating HCC in clinical trials, enhanced the effects of sorafenib, but also activated the c‐Met pathway in sorafenib‐resistant cells. Dual inhibition of Akt and c‐Met by their respective inhibitors, MK2206 and capmatinib, additively or synergistically suppressed sorafenib‐resistant HCC cells in vitro and sorafenib‐resistant HCC xenografts in mice. The anticancer activities of MK2206 mainly rely on its ability to induce cell apoptosis and autophagic death, while capmatinib treatment leads to cell cycle arrest at phase G1. These results provide strong evidence for further investigation on the clinical utility of dual inhibition of Akt and c‐Met, particularly MK2206 and capmatinib, as a second‐line therapy for advanced HCC that has acquired resistance to sorafenib.

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

Cited by 238 publications

References 48 publications

Ubenimex enhances the radiosensitivity of renal cell carcinoma cells by inducing autophagic cell death

Ubenimex enhances the radiosensitivity of renal cell carcinoma cells by inducing autophagic cell death

Depletion of histone deacetylase 1 inhibits metastatic abilities of gastric cancer cells by regulating the miR-34a/CD44 pathway

Dual inhibition of Akt and c‐Met as a second‐line therapy following acquired resistance to sorafenib in hepatocellular carcinoma cells

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