Bcl-2 Family Proteins Are Involved in the Signal Crosstalk between Endoplasmic Reticulum Stress and Mitochondrial Dysfunction in Tumor Chemotherapy Resistance

Su, Jing; Zhou, Lei; Xia, Meihui; Xu, Ye; Xiang, Xiyan; Sun, Liankun

doi:10.1155/2014/234370

Cited by 39 publications

(38 citation statements)

References 43 publications

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“…CHOP-knockdown cells are resistant to cell apoptosis that is usually induced by ERS [16], that can lead to various processes, including autophagy and apoptosis, which function as the regulators of cell survival and death [19, 20]. ERS can also activate the unfolded protein response, which reports have earmarked due to their role in chemotherapeutic resistance or antitumor therapy based on the stimuli and cell context [51]. GRP78, a molecular chaperone protein and a member of the heat shock protein-70 family, is critical for tumor progression and chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Promotes Autophagy and Apoptosis and Reduces Chemotherapy Resistance in Mutant p53 Lung Cancer Cells

Gan

Zhou

Zhong

et al. 2017

Cell Physiol Biochem

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Background/Aims: Lung cancer (LC) continues to be one of the most prevalent cancers around the world. During this study we aimed to investigate the involvement of endoplasmic reticulum stress (ERS) in autophagy, apoptosis, and chemotherapy resistance of mutant p53 LC cells. Methods: Immunohistochemistry was employed to help determine the p53 mutation status of cancer cells from 92 primary LC patients, who were subsequently assigned to either the mutant p53 (n = 39) or wild-type p53 group (n = 53). Results: Mutant p53 cells exhibited increased expression of the C/EBP homologous protein (CHOP), glucose-regulated protein 78 (GRP78), and inositol-requiring enzyme-1α (IRE1α). The Mutant p53 cells were also found to be sensitive to chemotherapy and displayed decreased expression of PI3K, Akt, and mTOR. The mutant p53 cell lines were treated with tunicamycin to induce ERS and rapamycin in order to inhibit mTOR. Both agents increased the expression of CHOP, GRP78, IRE1α, LC3-II/LC3-I, Atg5, Atg7, caspase-3, caspase-12, cleaved caspase-3, cleaved caspase-12, as well as decreases in cell proliferation as well as the expression levels of PI3K, Akt, and mTOR. Enhanced levels of cell apoptosis and reduced chemotherapy resistance were also detected. Conclusion: The findings of our study suggest that ERS promotes autophagy and apoptosis, while acting to reduce chemotherapy resistance in mutant p53 LC cells by downregulating the PI3K/Akt/mTOR signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Promotes Autophagy and Apoptosis and Reduces Chemotherapy Resistance in Mutant p53 Lung Cancer Cells

Gan

Zhou

Zhong

et al. 2017

Cell Physiol Biochem

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“…Bcl-2 anti-apoptotic proteins are located both in the MOM and ER nuclear envelope [94, 95]. Moreover, the pro-apoptotic Bax-like proteins, including BAX and BAK, are also localized in the ER membrane.…”

Section: Mechanisms Of Endoplasmatic Reticulum Stress-induced Apopmentioning

confidence: 99%

The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress

Rozpędek¹,

Pytel

Mucha³

et al. 2016

CMM

572

409

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Hypoxia is a major hallmark of the tumor microenvironment that is strictly associated with rapid cancer progression and induction of metastasis. Hypoxia inhibits disulfide bond formation and impairs protein folding in the Endoplasmic Reticulum (ER). The stress in the ER induces the activation of Unfolded Protein Response (UPR) pathways via the induction of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result, the level of phosphorylated Eukaryotic Initiation Factor 2 alpha (eIF2α) is markedly elevated, resulting in the promotion of a pro-adaptive signaling pathway by the inhibition of global protein synthesis and selective translation of Activating Transcription Factor 4 (ATF4). On the contrary, during conditions of prolonged ER stress, pro-adaptive responses fail and apoptotic cell death ensues. Interestingly, similar to the activity of the mitochondria, the ER may also directly activate the apoptotic pathway through ER stress-mediated leakage of calcium into the cytoplasm that leads to the activation of death effectors. Apoptotic cell death also ensues by ATF4-CHOP- mediated induction of several pro-apoptotic genes and suppression of the synthesis of anti-apoptotic Bcl-2 proteins. Advancing molecular insight into the transition of tumor cells from adaptation to apoptosis under hypoxia-induced ER stress may provide answers on how to overcome the limitations of current anti-tumor therapies. Targeting components of the UPR pathways may provide more effective elimination of tumor cells and as a result, contribute to the development of more promising anti-tumor therapeutic agents.

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“…The overexpression of anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein members such as Bcl-2/Bcl-xL/Mcl-1 frequently occurs in human cancers and is closely associated with cancer development and resistance to chemotherapies (1,2). By competing with anti-apoptotic Bcl-2 proteins, Bcl-2 homology domain 3 (BH3) mimetics induce cell death in a wide range of cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

SIRT3 participates in glucose metabolism interruption and apoptosis induced by BH3 mimetic S1 in ovarian cancer cells

Xiang

Kang

Yang

et al. 2016

International Journal of Oncology

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The Bcl-2 antiapoptotic proteins are important cancer therapy targets; however, their role in cancer cell metabolism remains unclear. We found that the BH3-only protein mimetic S1, a novel pan Bcl-2 inhibitor, simultaneously interrupted glucose metabolism and induced apoptosis in human SKOV3 ovarian cancer cells, which was related to the activation of SIRT3, a stress-responsive deacetylase. S1 interrupted the cellular glucose metabolism mainly through causing damage to mitochondrial respiration and inhibiting glycolysis. Moreover, S1 upregulated the gene and protein expression of SIRT3, and induced the translocation of SIRT3 from the nucleus to mitochondria. SIRT3 silencing reversed the effects of S1 on glucose metabolism and apoptosis through increasing the level of HK-II localized to the mitochondria, while a combination of the glycolysis inhibitor 2-DG and S1 intensified the cytotoxicity through further upregulation of SIRT3 expression. This study underscores an essential role of SIRT3 in the antitumor effect of Bcl-2 inhibitors in human ovarian cancer through regulating both metabolism and apoptosis. The manipulation of Bcl-2 inhibitors combined with the use of classic glycolysis inhibitors may be rational strategies to improve ovarian cancer therapy.

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Bcl-2 Family Proteins Are Involved in the Signal Crosstalk between Endoplasmic Reticulum Stress and Mitochondrial Dysfunction in Tumor Chemotherapy Resistance

Cited by 39 publications

References 43 publications

Endoplasmic Reticulum Stress Promotes Autophagy and Apoptosis and Reduces Chemotherapy Resistance in Mutant p53 Lung Cancer Cells

Endoplasmic Reticulum Stress Promotes Autophagy and Apoptosis and Reduces Chemotherapy Resistance in Mutant p53 Lung Cancer Cells

The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress

SIRT3 participates in glucose metabolism interruption and apoptosis induced by BH3 mimetic S1 in ovarian cancer cells

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