RACK1 induces chemotherapy resistance in esophageal carcinoma by upregulating the PI3K/AKT  pathway and Bcl-2 expression

Liu, Bowen; Chen, Pengxiang; Cheng, Bo; Cheng, Yufeng

doi:10.2147/ott.s152818

Cited by 36 publications

(29 citation statements)

References 29 publications

(30 reference statements)

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“…Interestingly, recent studies have shown that Rack1 also confers resistance to cancer. Rack1 elevation enhances chemoresistance in leukemia, hepatocellular carcinoma, and esophageal cancer [39,41,43]; Rack1 overexpression promotes targeted therapy resistance in gastrointestinal stromal tumor [42]. These findings indicate that Rack1 might also be a critical hub involved in the crosstalk between drug resistance and invasion/metastasis.…”

Section: Discussionmentioning

confidence: 87%

“…In particular, higher Rack1 level is an independent predictor for poor prognosis in breast cancer. Recently, Rack1 has been reported to be a key protein involved in drug resistance in several carcinomas [39][40][41][42][43]. These findings have suggested that Rack1 may act as an important convergence point for drug resistance and invasion/metastasis.…”

Section: Introductionmentioning

confidence: 97%

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Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

Fan

et al. 2019

Breast Cancer Res

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Background: Acquirement of resistance is always associated with a highly aggressive phenotype of tumor cells. Recent studies have revealed that Annexin A2 (Anxa2) is a key protein that links drug resistance and cancer metastasis. A high level of Anxa2 in cancer tissues is correlated to a highly aggressive phenotype. Increased Anxa2 expression appears to be specific in many drug-resistant cancer cells. The functional activity of Anxa2 is regulated by tyrosine phosphorylation at the Tyr23 site. Nevertheless, the accurate molecular mechanisms underlying the regulation of Anxa2 tyrosine phosphorylation and whether phosphorylation is necessary for the enhanced invasive phenotype of drug-resistant cells remain unknown. Methods: Small interfering RNAs, small molecule inhibitors, overexpression, loss of function or gain of function, rescue experiments, Western blot, wound healing assays, transwell assays, and in vivo metastasis mice models were used to investigate the functional effects of Rack1 and Src on the tyrosine phosphorylation of Anxa2 and the invasion and metastatic potential of drug-resistant breast cancer cells. The interaction among Rack1, Src, and Anxa2 in drug-resistant cells was verified by co-immunoprecipitation assay. Results: We demonstrated that Anxa2 Tyr23 phosphorylation is necessary for multidrug-resistant breast cancer invasion and metastasis. Rack1 is required for the invasive and metastatic potential of drug-resistant breast cancer cells through modulating Anxa2 phosphorylation. We provided evidence that Rack1 acts as a signal hub and mediates the interaction between Src and Anxa2, thereby facilitating Anxa2 phosphorylation by Src kinase. Conclusions: Our findings suggest a convergence point role of Rack1/Src/Anxa2 complex in the crosstalk between drug resistance and cancer aggressiveness. The interaction between Anxa2 and Rack1/Src is responsible for the association between drug resistance and invasive/metastatic potential in breast cancer cells. Thus, our findings provide novel insights on the mechanism underlying the functional linkage between drug resistance and cancer aggressiveness.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 97%

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

Fan

et al. 2019

Breast Cancer Res

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“…PI3K translocates to the plasma membrane and subsequently phosphorylates AKT. As a key effector of PI3K, AKT also regulates various cellular responses, including cell proliferation and cell survival (41)(42)(43), and can sustain Bcl-2 expression in certain diseases (44,45). Previous studies have shown that v-3 FAs promoted the activation of ERK and PI3K/AKT pathways mainly via GPR120, exerting the antiapoptotic effect in certain cell lines (19,30,46,47).…”

Section: Discussionmentioning

confidence: 99%

Activation of the Omega-3 Fatty Acid Receptor GPR120 Protects against Focal Cerebral Ischemic Injury by Preventing Inflammation and Apoptosis in Mice

Ren

Chen

Wang

et al. 2019

The Journal of Immunology

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G protein–coupled receptor 120 (GPR120) has been shown to negatively regulate inflammation and apoptosis, but its role in cerebral ischemic injury remains unclear. Using an in vivo model of middle cerebral artery occlusion (MCAO) and an in vitro model of oxygen-glucose deprivation (OGD), we investigated the potential role and molecular mechanisms of GPR120 in focal cerebral ischemic injury. Increased GPR120 expression was observed in microglia and neurons following MCAO-induced ischemia in wild type C57BL/6 mice. Treatment with docosahexaenoic acid (DHA) inhibited OGD-induced inflammatory response in primary microglia and murine microglial BV2 cells, whereas silencing of GPR120 strongly exacerbated the inflammation induced by OGD and abolished the anti-inflammatory effects of DHA. Mechanistically, DHA inhibited OGD-induced inflammation through GPR120 interacting with β-arrestin2. In addition to its anti-inflammatory function, GPR120 also played a role in apoptosis as its knockdown impaired the antiapoptotic effect of DHA in OGD-induced rat pheochromocytoma (PC12) cells. Finally, using MCAO mouse model, we demonstrated that GPR120 activation protected against focal cerebral ischemic injury by preventing inflammation and apoptosis. Our study indicated that pharmacological targeting of GPR120 may provide a novel approach for the treatment of patients with ischemic stroke.

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“…In the present study, the optimized concentration and treatment time of DDP for use in vitro were determined by MTT assay; 1.5x10 -5 M DDP treatment for 24 h was selected for further investigation. The optimized concentration (1.5x10 -5 M) in the study is similar to the clinically used dose of DDP (20 mg/m 2 /day) (38,39). The effect of CtBP2 on the cell apoptosis induced by DDP was investigated by Hoechst 33342 staining and FCM.…”

Section: Discussionmentioning

confidence: 99%

C-terminal binding protein‑2 mediates cisplatin chemoresistance in esophageal cancer cells via the inhibition of apoptosis

Shi

Mao

et al. 2018

Int J Oncol

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C-terminal binding protein‑2 (CtBP2) is a transcriptional co-repressor that is associated with tumorigenesis and tumor progression. It has been reported to predict a poor prognosis in several human cancers, including esophageal squamous cell carcinoma (ESCC). The present study aimed to investigate the involvement of CtBP2 in the cisplatin (DDP) resistance of the ECA109 ESCC cell line and its effect on the expression of apoptosis-associated proteins. Constructed recombinant lentiviruses were used for the knockdown or overexpression of CtBP2 in ECA109 cells, and the expression of CtBP2 was measured using reverse transcription-quantitative polymerase chain reaction and western blotting following transfection. MTT assays, Hoechst 33342 staining and flow cytometry (FCM) were applied to detect the influence of CtBP2 on the DDP-induced viability and apoptosis of the transfected ECA109 cells. In addition, the levels of apoptosis-associated proteins, including p53, B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax) and activated caspase-3 were investigated in the transfected ECA109 cells. Stable ECA109 cells with CtBP2 overexpression or knockdown were successfully established. The results of the MTT, Hoechst 33342 and FCM assays demonstrated that overexpression of CtBP2 attenuated the reduction of cell viability and inhibited the cell apoptosis induced by DDP. Furthermore, the western blotting results indicated that CtBP2 overexpression inhibited the DDP-induced apoptosis of ECA109 cells via the reduction of p53, activated caspase-3 and Bax expression, and promotion of Bcl‑2 expression. Therefore, the present study indicated that CtBP2 reduced the susceptibility of ECA109 cells to DDP by regulating the expression of apoptosis-related proteins, suggesting that it may be a promising therapeutic target in ESCC in the future.

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RACK1 induces chemotherapy resistance in esophageal carcinoma by upregulating the PI3K/AKT pathway and Bcl-2 expression

Cited by 36 publications

References 29 publications

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

Activation of the Omega-3 Fatty Acid Receptor GPR120 Protects against Focal Cerebral Ischemic Injury by Preventing Inflammation and Apoptosis in Mice

C-terminal binding protein‑2 mediates cisplatin chemoresistance in esophageal cancer cells via the inhibition of apoptosis

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