Bax deficiency mediated drug resistance can be reversed by endoplasmic reticulum stress induced death signaling

Chandrika, Bhavya Balan; Maney, Sathish Kumar; Lekshmi, Swathi U.; Joseph, Jeena; Seervi, Mahendra; Koganti, Praveen; Santhoshkumar, T.R.

doi:10.1016/j.bcp.2010.01.032

Cited by 19 publications

(15 citation statements)

References 36 publications

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“…The insulin resistant state was accompanied by hyperinsulinemia and abnormal glucose metabolism, both of which can induce ER stress by stimulating mitochondria to produce RoS. ER stress then inhibits insulin and reduces the expression of GLUTs, exacerbating IR [1,28,[31][32][33][34][35][36]. In this study, early IR was accompanied by increased production of intracellular RoS and decreased MMP, resulting in oxidative and ER stress.…”

Section: Discussionmentioning

confidence: 59%

“…Under normal conditions, hepatocellular carcinoma cells are not sensitive to chemoand radiotherapy, characterized by drug resistance and poor systemic effects of therapies. This may be due to the state of chronic stress caused by the liver tumor microenvironment, including underdeveloped vessels, anoxia, low glucose, and low pH [28,[32][33][34][35][36][39][40][41][42].…”

Section: Discussionmentioning

confidence: 99%

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The endoplasmic reticulum stress response is associated with insulin resistance-mediated drug resistance in HepG2 cells

L¹,

G²,

Wei³

et al. 2015

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Insulin resistance has a close relationship with tumorigenesis, tumor progression, and cancer prognosis. Importantly, the liver is the main target tissue of insulin, and the resistance to chemotherapeutic agents has been reported in hepatocarcinoma. However, little is known about the relationship between drug resistance and insulin resistance in hepatocarcinoma. Therefore, we treated HepG2 cells (a human hepatoma cell line) with high concentrations of insulin to establish a cell-based model of insulin resistance (HepG2/IR cells) to define the relationship between insulin resistance and the resistance to chemotherapy. We identified that HepG2/IR cells exhibited stable insulin resistance, with decreased glucose consumption, reduced glycogen synthesis, and decreased expression of the insulin receptor gene. HepG2/IR cells also exhibited endoplasmic reticulum (ER) dilatation and degranulation. Molecular markers of endoplasmic reticulum stress, including glucose-regulated protein78 (GRP78) and phosphorylated protein kinase R-like ER kinase (p-PERK), increased significantly, which was accompanied by increased reactive oxygen metabolism and decreased mitochondrial membrane potential. In addition, HepG2/IR cells were resistant to the chemotherapy agent Adriamycin, which was accompanied by the upregulation of multidrug resistance gene 1/ P-glycoprotein (P-gp; an endoplasmic reticulum chaperone that plays a role in ER stress), and enhanced drug efflux. These data suggest that the endoplasmic reticulum (ER) stress response was active in HepG2/IR cells, and that insulin resistance was related to drug resistance in HepG2 cells. Interestingly, the ER stress and chemotherapy resistance observed in HepG2/IR cells could be reversed by treatment with the insulin sensitizer pioglitazone. Therefore, our study suggests that there is a close relationship between the resistance to chemotherapy and insulin resistance in HepG2 cells, and that the ER stress response play a role in insulin resistance-mediated drug resistance in hepatocarcinoma cells.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

The endoplasmic reticulum stress response is associated with insulin resistance-mediated drug resistance in HepG2 cells

L¹,

G²,

Wei³

et al. 2015

neo

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“…53 Indeed, certain chemical apoptotic stimuli recruit alternative forms of cell death in the absence of Bax and Bak 54, 55 and molecules able to induce cyt c release in the absence of Bax have also been identified. 23 This is not the case in our system, where in absence of Bax in colorectal cancer cells, PGC1α is not anymore able to induce cyt c release, apoptosis and to oppose tumor growth. We therefore believe that, in the presence of Bax, the PGC1α-induced ROS accumulation represents one of the main apoptosis-driving factors in colorectal cancer cells, thus bona fide opening the avenue for novel therapeutic strategies for the treatment of colon cancer.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 60%

“…17,[19][20][21] On the other hand, the absence of Bax alone is not sufficient to block apoptosis 19,21,22 and several candidates have been proposed that could alternatively induce cyt c release in the absence of Bax. 23 The relationship between ROS and Bax protein activation has been widely investigated. It has been postulated that Bax acts upstream of ROS production and that Bax-induced ROS burst is both necessary and sufficient for cyt c redistribution in these cells.…”

Section: Pgc1α Induces Bax Activationmentioning

confidence: 99%

Bax is necessary for PGC1α pro-apoptotic effect in colorectal cancer cells

D'Errico¹,

Sasso²,

Salvatore³

et al. 2011

Cell Cycle

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“…26,27 Knowing that Grp78 has a role in ER stress, we investigated ER stress status in oridonin-treated HepG2 cells. Results showed that oridonin treatment activated ER stress.…”

Section: Discussionmentioning

confidence: 99%

Proteomic and Functional Analyses Reveal the Potential Involvement of Endoplasmic Reticulum Stress and α-CP1 in the Anticancer Activities of Oridonin in HepG2 Cells

et al. 2010

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Oridonin has been shown to exhibit therapeutic effects against hepatocellular carcinoma (HCC) in vitro and in vivo. This study aimed to identify the anti-HCC mechanisms of oridonin in HepG2 cells using proteomic and functional analyses. MTT assay showed that oridonin treatment for 24 hours dose-dependently inhibited cell growth with an IC 50 value of 40.4 mM. Treatment with 40 mM oridonin for 24 hours induced apoptosis determined by nuclear morphologic changes of DAPI-stained cells and flow cytometric analysis of annexin V-FITC/PI-stained cells, which was accompanied by Grp78 upregulation and a-CP1 downregulation identified by proteomic analysis. Immunoblot analysis for the endoplasmic reticulum (ER) stressrelated proteins demonstrated that the expression levels of phosphorylated PERK (p-PERK) and CHOP were increased, whereas PERK, ATF-6, and IRE-1 expression levels were decreased. Knockdown of a-CP1 expression with siRNA significantly increased cell death and apoptosis in control and oridonin-treated HepG2 cells. Together, these data provide proteomic and functional evidence for the potential involvement of ER stress and a-CP1 in the antiproliferative and apoptotic activities of oridonin in HepG2 cells, which shed new light on the action mechanisms of oridonin in HCC management.

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Bax deficiency mediated drug resistance can be reversed by endoplasmic reticulum stress induced death signaling

Cited by 19 publications

References 36 publications

The endoplasmic reticulum stress response is associated with insulin resistance-mediated drug resistance in HepG2 cells

The endoplasmic reticulum stress response is associated with insulin resistance-mediated drug resistance in HepG2 cells

Bax is necessary for PGC1α pro-apoptotic effect in colorectal cancer cells

Proteomic and Functional Analyses Reveal the Potential Involvement of Endoplasmic Reticulum Stress and α-CP1 in the Anticancer Activities of Oridonin in HepG2 Cells

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