The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular carcinoma cells

Cheng, Ping; Ni, Zhenhong; Dai, Xufang; Wang, Bin; Ding, Wei; Smith, Amber Rae; Xu, Liang; Wu, Dapeng; He, Fengtian; Lian, Jiqin

doi:10.1038/cddis.2013.17

Cited by 78 publications

(66 citation statements)

References 45 publications

(53 reference statements)

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“…Bcl-2 is associated with mitochondrial membrane potential and autophagy (20), and the present study demonstrated that expression of Bcl-2 increases following PAB treatment, possibly stabilizing the mitochondrial membrane potential. Furthermore, it has been reported that Bcl-2 inhibits autophagy through direct binding with Beclin-1 (24). By contrast, the PAB-induced Bcl-2 expression observed in the present study was also accompanied by enhanced autophagy.…”

Section: Discussioncontrasting

confidence: 64%

Pseudolaric acid B activates autophagy in MCF-7 human breast cancer cells to prevent cell death

Chen

et al. 2016

Oncology Letters

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Abstract. Pseudolaric acid B (PAB) has been demonstrated to exert antitumor effects in MCF-7 human breast cancer cells. The present study aimed to investigate the mechanism of resistance to PAB-induced cell death. Following incubation with 4 µM of PAB for 3 days, the majority of MCF-7 cells became senescent, while some retained the same morphology as control cells, as assessed using a senescence detection kit. Additionally, 36 h of treatment with 4 µM of PAB increased the positive staining of autophagy markers, as shown by monodansylcadaverine and acridine orange staining. Western blot analysis indicated that this treatment also increased expression of the autophagy-related proteins Beclin-1 and microtubule-associated protein 1 light chain 3. Furthermore, treatment with PAB and the autophagy inhibitor 3-methyl adenine significantly decreased the ratio of autophagy, as assessed by flow cytometric analysis of monodansylcadaverine staining density (P<0.001), and increased the ratio of cell death, as assessed by MTT analysis (P<0.001). This indicated that autophagy promotes cell survival as a resistance mechanism to PAB treatment. Additionally, the present study demonstrated that PAB treatment did not affect the mitochondrial membrane potential, which may be related to autophagy. Increased Bcl-2 expression may explain why PAB did not affect the mitochondrial membrane potential. A Bcl-2 binding test demonstrated that PAB treatment inhibits the binding of Bcl-2 and Beclin-1, which may free Beclin-1 to participate in autophagy. Therefore, the present study demonstrated that autophagy may be activated by PAB treatment in human breast cancer MCF-7 cells, contributing to resistance to cell death.

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Section: Discussioncontrasting

confidence: 64%

Pseudolaric acid B activates autophagy in MCF-7 human breast cancer cells to prevent cell death

Chen

et al. 2016

Oncology Letters

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“…The generation of ROS by anticancer agents has been reported to mediate autophagy in previous studies (25)(26)(27)(28)(29). ROS have been shown to induce autophagy by several processes: activating ERK and JNK, inhibiting mTOR signaling by activating AMP-activated protein kinase (AMPK), and promoting the translocation of oxidative HMGB1 from nucleus to cytoplasm.…”

Section: Discussionmentioning

confidence: 98%

Autophagy inhibition enhances sensitivity of endometrial carcinoma cells to paclitaxel

Liu

2015

International Journal of Oncology

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Abstract. Autophagy has been shown to be involved in cancer cell resistance to chemotherapy. Paclitaxel, a widely used chemotherapeutic drug, was demonstrated to induce autophagy in various cancer cells. Therefore, we sought to evaluate the role of autophagy on the paclitaxel-induced cell death in endometrial carcinoma. In this study, we found that paclitaxel induced autophagy in paclitaxel-insensitive HEC-1A and JEC cells, exhibiting an increased microtubule associated protein 1 light chain 3 (LC3)-II/LC3-I ratio, a decrease in p62/ SQSTM1 abundance, the upregulation of Beclin 1 expression and punctate dots of yellow fluorescent protein (YFP)-LC3 in the cytosol. Paclitaxel-mediated cell death was further potentiated by pretreatment with autophagy inhibitor chloroquine (CQ) or shRNA against the autophagic gene beclin 1. Moreover, paclitaxel stimulated reactive oxygen species (ROS) generation, and inhibition of the ROS by antioxidant N-acetyl-cysteine (NAC) blocked paclitaxel-induced autophagy, indicating that paclitaxel-induced autophagy in endometrial carcinoma cells is mediated by ROS. These findings suggest that paclitaxelelicited autophagic response plays a protective role that impedes the eventual death of endometrial carcinoma cell, and that autophagy-inhibitor therapy could be an effective and potent strategy to improve paclitaxel treatment outcomes in the treatment of endometrial carcinoma.

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“…39 The total cell death rate (%) D numbers of dead cells/(numbers of living cells C numbers of dead cells) £ 100.…”

Section: Trypan Blue Exclusion Assaymentioning

confidence: 99%

“…Subsequently, western blot analysis was performed as described previously. 39 Primary antibodies of anti-MAP1LC3 (L7543) and anti-ATG4B (A2981) were purchased from Sigma; anti-PARP (5625), anti-SQSTM1 (5114), anti-ATG3 (3415), and anti-PIK3C3 (3811) were from Cell Signaling Technology; anti-ATG12 (ab109492), anti-ATG16L1 (ab47946), anti-ATG5 (ab108327), anti-ATG7 (ab52472) and anti-ATG10 (ab124711) were from Abcam; anti-BECN1 (sc-11427) and anti-TUBA (sc-5546) were from Santa Cruz Biotechnology.…”

Section: Western Blot Analysismentioning

confidence: 99%

Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin

Yan

et al. 2016

Autophagy

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Pirarubicin (THP) is a newer generation anthracycline anticancer drug. In the clinic, THP and THP-based combination therapies have been demonstrated to be effective against various tumors without severe side effects. However, previous clinical studies have shown that most patients with cervical cancer are not sensitive to THP treatment, and the associated mechanisms are not clear. Consistent with the clinical study, we confirmed that cervical cancer cells were resistant to THP in vitro and in vivo. Our data demonstrated that THP induced a protective macroautophagy/autophagy response in cervical cancer cells, and suppression of this autophagy dramatically enhanced the cytotoxicity of THP. By scanning the mRNA level change of autophagy-related genes, we found that the upregulation of ATG4B (autophagyrelated 4B cysteine peptidase) plays an important role in THP-induced autophagy. Moreover, THP increased the mRNA level of ATG4B in cervical cancer cells by promoting mRNA stability without influencing its transcription. Furthermore, THP triggered a downregulation of MIR34C-5p, which was associated with the upregulation of ATG4B and autophagy induction. Overexpression of MIR34C-5p significantly decreased the level of ATG4B and attenuated autophagy, accompanied by enhanced cell death and apoptosis in THP-treated cervical cancer cells. These results for the first time reveal the presence of a MIR34C-5p-ATG4B-autophagy signaling axis in THP-treated cervical cancer cells in vitro and in vivo, and the axis, at least partially, accounts for the THP nonsensitivity in cervical cancer patients. This study may provide a new insight for improving the chemotherapeutic effect of THP, which may be beneficial to the further clinical application of THP in cervical cancer treatment.

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The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular carcinoma cells

Cited by 78 publications

References 45 publications

Pseudolaric acid B activates autophagy in MCF-7 human breast cancer cells to prevent cell death

Pseudolaric acid B activates autophagy in MCF-7 human breast cancer cells to prevent cell death

Autophagy inhibition enhances sensitivity of endometrial carcinoma cells to paclitaxel

Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin

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