Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells

Yu, Lin; Wang, Ziqiang; Liu, Lunxu; Chen, Long-Qi

doi:10.1016/j.lungcan.2010.06.004

Cited by 80 publications

(66 citation statements)

References 27 publications

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“…This suggests that P-AKT activation is a secondary event during ER stress mediated chemoresistance in PDAC. Our findings are supported by work showing that inhibition of AKT phosphorylation has only a limited impact on cisplatin resistance caused by ER stress tolerance in lung cancer (34). Taken together, these results indicate that although GRP78-mediated P-AKT activation contributes to GEM resistance in PDAC cells, future studies are necessary to shed light on the additional downstream targets of GRP78 that may play a role in ER stress mediated chemoresistance.…”

Section: Discussionsupporting

confidence: 81%

Expression of GRP78, Master Regulator of the Unfolded Protein Response, Increases Chemoresistance in Pancreatic Ductal Adenocarcinoma

Gifford

Huang

Zeleniak

et al. 2016

Molecular Cancer Therapeutics

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The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is dismal. Although gemcitabine (GEM) is the standard chemotherapeutic agent for adjuvant therapy of resectable PDAC, recurrent disease is observed in an alarming number of GEM-treated patients. Regardless of the adjuvant therapy, the vast majority of patients treated with chemotherapy after surgical resection show tumor recurrence. A better understanding of the molecular mechanisms that contribute to chemoresistance would aid the development of more effective treatment strategies. GRP78 is an endoplasmic reticulum (ER) chaperone protein that primarily resides in the lumen of the ER and is the master regulator of the unfolded protein response (UPR). Here, we report that expression of GRP78 is significantly higher in GEM-resistant PDAC compared to GEM-sensitive PDAC patient samples. We show that GRP78 induces chemoresistance in PDAC cells. Our results also show that knockdown of GRP78 reduces chemoresistance in PDAC. Finally, we found that IT-139, a ruthenium-based anticancer drug, can overcome GRP78-mediated chemoresistance. In vitro, IT-139 restores sensitivity to cytotoxic drugs in drug-resistant PDAC cells and induces twice as much cell death in combination treatment compared with GEM alone. In vivo, a single weekly IT-139 treatment in combination with GEM caused a 35% increase in median survival and a 25% increase in overall survival compared to GEM alone. Collectively, our data show that GRP78 expression promotes chemoresistance in PDAC and therapeutic strategies, blocking the activity of GRP78 increases the efficacy of currently available therapies.

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Section: Discussionsupporting

confidence: 81%

Expression of GRP78, Master Regulator of the Unfolded Protein Response, Increases Chemoresistance in Pancreatic Ductal Adenocarcinoma

Gifford

Huang

Zeleniak

et al. 2016

Molecular Cancer Therapeutics

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“…Interestingly, it is know that there is a tight connection between GRP78 and the PI3K/AKT pathway. Indeed, AKT can be a downstream target of GRP78 and on another hand AKT controls also GRP78 levels (Dai et al, 2010;Lin et al, 2011). We analyzed the phosphorylation status of AKT upon DMC treatment (phosphorylation at Thr308) (Supplemental Fig.…”

Section: Dmc Induces Apoptosis and Cell Cycle Alterations In Leukemiamentioning

confidence: 99%

“…The ability of DMC and OSU-03012 to inhibit AKT activity (Wang et al, 2008;Fan et al, 2011) may give part of the answer. Indeed, PI3K/AKT pathway can prevent ER stress through an accumulation of GRP78 (Dai et al, 2010), and, on the other hand, AKT is also activated by GRP78 (Lin et al, 2011). Therefore, the inhibition of AKT by DMC or OSU-03012 may account for the induction of ER stress in cancer cells.…”

Section: Dmc Induces Apoptosis and Cell Cycle Alterations In Leukemiamentioning

confidence: 99%

2,5-Dimethyl-Celecoxib Inhibits Cell Cycle Progression and Induces Apoptosis in Human Leukemia Cells

Sobolewski

Rhim

Legrand

et al. 2015

J Pharmacol Exp Ther

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Cyclooxygenase-2 (COX-2) is an essential regulator of cancer promotion and progression. Extensive efforts to target this enzyme have been developed to reduce growth of cancer cells for chemopreventive and therapeutic reasons. In this context, cyclooxygenase-2 inhibitors present interesting antitumor effects. However, inhibition of COX-2 by anti-COX-2 compounds such as celecoxib was recently associated with detrimental cardiovascular side effects limiting their clinical use. As many anticancer effects of celecoxib are COX-2 independent, analogs such as 2,5-dimethyl-celecoxib (DMC), which lacks COX-2-inhibitory activity, represent a promising alternative strategy. In this study, we investigated the effect of this molecule on growth of hematologic cancer cell lines (U937, Jurkat, Hel, Raji, and K562). We found that this molecule is able to reduce the growth and induces apoptosis more efficiently than celecoxib in all the leukemic cell lines tested. Cell death was associated with downregulation of Mcl-1 protein expression. We also found that DMC induces endoplasmic reticulum stress, which is associated with a decreased of GRP78 protein expression and an alteration of cell cycle progression at the G1/S transition in U937 cells. Accordingly, typical downregulation of c-Myc and cyclin D1 and an upregulation of p27 were observed. Interestingly, for shorter time points, an alteration of mitotic progression, associated with the downregulation of survivin protein expression was observed. Altogether, our data provide new evidence about the mode of action of this compound on hematologic malignancies.

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“…Moreover, these cells are cisplatin-resistant. Compared to the parental cells, H460et and A549et cells led to significant GRP78 upregulation and high levels of phospho-Akt, indicating that cisplatin resistance was associated with ER stress and Akt activation (32). It was also reported that gene silencing of N-ethylmaleimide-sensitive factor attachment protein α (NAPA), which is involved in protein transfer in the ER, rendered tumor cells sensitive to cisplatin and overcame drug resistance in vitro and in vivo (33).…”

Section: The Prosurvival Role Of Er Stress Causes Cisplatin Drug Resimentioning

confidence: 99%

A new strategy of promoting cisplatin chemotherapeutic efficiency by targeting endoplasmic reticulum stress

Wang

2013

Molecular and Clinical Oncology

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Abstract. Cisplatin (cis-diamminedichloroplatinum II, CDDP) is one of the most effective chemotherapeutic agents and is widely used in the treatment of solid tumors. However, its side effects and acquired resistance gained during the course of treatment may limit its usage. It is generally considered to be a cytotoxic drug that kills cancer cells by damaging their DNA and inhibiting DNA synthesis to induce apoptosis via the mitochondrial death pathway or through plasma membrane disruption, triggering the Fas death receptor pathway. The endoplasmic reticulum (ER) is one of the most important protein-folding compartments within the cell and an intracellular Ca 2+ storage organelle. The ER contains a number of molecular chaperones, which may play an important role in determining cellular sensitivity to ER stress and apoptosis. The aim of this review was to summarize our current understanding regarding the mechanisms of ER stress response by which cisplatin induces cell death and the basis for cisplatin resistance. Various aspects were addressed, including the two-way regulation of ER stress, the involvement of ER stress in cisplatin-induced cell death and drug resistance and the drugs enhancing cisplatin-induced cell death by interfering with ER stress. An understanding of how ER stress signaling pathways regulate cisplatin-induced cell death may enable the development of more effective therapeutic strategies for the treatment of cancer.

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Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells

Cited by 80 publications

References 27 publications

Expression of GRP78, Master Regulator of the Unfolded Protein Response, Increases Chemoresistance in Pancreatic Ductal Adenocarcinoma

Expression of GRP78, Master Regulator of the Unfolded Protein Response, Increases Chemoresistance in Pancreatic Ductal Adenocarcinoma

2,5-Dimethyl-Celecoxib Inhibits Cell Cycle Progression and Induces Apoptosis in Human Leukemia Cells

A new strategy of promoting cisplatin chemotherapeutic efficiency by targeting endoplasmic reticulum stress

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