Sestrin2 and sestrin3 suppress NK-92 cell-mediated cytotoxic activity on ovarian cancer cells through AMPK and mTORC1 signaling

Wang, Xuejin; Liu, Weifeng; Zhuang, Deyi; Hong, Shaoxian; Chen, Jingfang

doi:10.18632/oncotarget.21487

Cited by 19 publications

(15 citation statements)

References 41 publications

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“…Physiologically, activated sestrins suppress oxidative stress by reduction of ROS level and inhibition of a mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway [29]. Compelling evidence demonstrates that a dysregulation of intracellular ROS homeostasis plays an important role in the development and metastatic dissemination of cancerous cells [5, 13, 30–32]. Increasing ROS level contributes to achieving anoikis resistance of cancerous cells, which is a crucial step during metastatic colonization [5].…”

Section: Discussionmentioning

confidence: 99%

Interactions between microRNA-200 family and Sestrin proteins in endometrial cancer cell lines and their significance to anoikis

et al. 2019

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In the present study, we intend to determine whether Sestrin proteins 1, 2, and 3 (SESN1-3) are targets of microRNA-200 family (miR-200) in endometrial cancer (EC) Ishikawa, AN3CA, KLE, and RL 95-2 cell lines and to investigate how these potential interactions influence anoikis resistance of EC cell lines. The luciferase reporter assay, qRT-PCR, and western blotting assays were used to verify whether SESN1-3 are direct targets of miR-200. Moreover, the anoikis assay and transient transfections of miR-200 mimics or inhibitors into EC cell lines were performed to evaluate the modulatory role of miR-200 and SESN proteins on anoikis resistance. We demonstrated that SESN2 protein is a direct target of mir-141 in KLE and RL-95-2 EC cell lines and the functional interaction of miR-141 and SESN2 protein has a downstream effect on anoikis resistance and SESN2 expression level in Ishikawa and AN3CA cell lines. Moreover, we have shown that SESN3 protein is a direct target of miR-200b, miR-200c, and miR-429 in Ishikawa, AN3CA, and KLE cell lines. Our results show that manipulation of miR-200b, miR-200c, and miR-429 expression patterns also has an influence on anoikis resistance in EC cell lines. In conclusion, we identified new interactions between miR-200 and the oxidative stress response SESN proteins that affect anoikis resistance in human EC cells.

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Section: Discussionmentioning

confidence: 99%

Interactions between microRNA-200 family and Sestrin proteins in endometrial cancer cell lines and their significance to anoikis

et al. 2019

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“…13 Moreover, SESN2 was ascribed to promoting the survival and proliferation of ovarian cancer cells by suppressing cytotoxicity of natural killer cells via AMPK. 22 Thus, SESN2 has exerted its pivotal role in mediating tumor progression via AKT and AMPK. To date, several lines of evidence showed contradictive pathogenic role of SESN2 in HCC.…”

Section: Introductionmentioning

confidence: 99%

Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma

et al. 2018

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Hepatocellular carcinoma (HCC) is the malignancy derived from normal hepatocytes with increasing incidence and extremely poor prognosis worldwide. The only approved first‐line systematic treatment agent for HCC, sorafenib, is capable to effectively improve advanced HCC patients’ survival. However, it is gradually recognized that the therapeutic response to sorafenib could be drastically diminished after short‐term treatment, defined as primary resistance. The present study is aimed to explore the role of stress‐inducible protein Sestrin2 (SESN2), one of the most important sestrins family members, in sorafenib primary resistance. Herein, we initially found that SESN2 expression was significantly up‐regulated in both HCC cell lines and tissues compared to normal human hepatocytes and corresponding adjacent liver tissues, respectively. In addition, SESN2 expression was highly correlated with sorafenib IC50 of HCC cell lines. Thereafter, we showed that sorafenib treatment resulted in an increase of SESN2 expression and the knockdown of SESN2 exacerbated sorafenib‐induced proliferation inhibition and cell apoptosis. Further mechanistic study uncovered that SESN2 deficiency impaired both AKT and AMPK phosphorylation and activation after sorafenib treatment. Moreover, the correlations between SESN2 expression and both phosphor‐AKT and phosphor‐AMPK expression were illustrated in HCC tissues. Taken together, our study demonstrates that SESN2 activates AKT and AMPK signaling as a novel mechanism to induce sorafenib primary resistance in HCC.

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“…The possible role of SESN2 in innate and adaptive immune cells, including monocytes, macrophages, natural killer (NK) cells, and T lymphocytes, has been increasingly recognized (11, 12, 17, 92). The expression and effect of SESN2 on immune cells in response to various stimuli are described in Figure 4.…”

Section: Sesn2 and Immune Cellsmentioning

confidence: 99%

“…The NK-92 cell line has high tumoral potency and is widely used for immunotherapy in cancer (97). In an ovarian cancer xenograft mouse model, Wang et al (92) first identified that SESN2 and SESN3 expression was much higher in intratumoral NK-92 cells than in normal human blood NK cells. Overexpression of SESN2 or SESN3 could inhibit NK-92 cell-mediated cytotoxic activation through the activation of AMPK and the suppression of mTORC1, which manifested as decreases in the natural cytotoxicity receptors (NKp44 and NKG2D) and cytotoxic factor (TNF-α) and weakened the antitumor activity of NK-92 cells, emphasizing the potential effect of SESNs on immunotherapy in cancer.…”

Section: Sesn2 and Immune Cellsmentioning

confidence: 99%

Sestrin2: Its Potential Role and Regulatory Mechanism in Host Immune Response in Diseases

2019

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Sestrin2 (SESN2), a highly evolutionarily conserved protein, is critically involved in cellular responses to various stresses. SESN2 has a protective effect on physiological and pathological states mainly via regulating oxidative stress, endoplasmic reticulum stress, autophagy, metabolism, and inflammation. In recent years, breakthrough investigations with regard to the regulation and signaling mechanisms of SESN2 have markedly deepened our understanding of its potential role as well as its significance in host response. However, the functions of SESN2 in the immune system and inflammation remain elusive. It has been documented that many immune cells positively express SESN2 and, in turn, that SESN2 might modulate cellular activities. This review incorporates recent progress and aims to provide novel insight into the protective role and regulatory pathway of SESN2, which acts as a potential biomarker and therapeutic target in the context of various diseases.

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Sestrin2 and sestrin3 suppress NK-92 cell-mediated cytotoxic activity on ovarian cancer cells through AMPK and mTORC1 signaling

Cited by 19 publications

References 41 publications

Interactions between microRNA-200 family and Sestrin proteins in endometrial cancer cell lines and their significance to anoikis

Interactions between microRNA-200 family and Sestrin proteins in endometrial cancer cell lines and their significance to anoikis

Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma

Sestrin2: Its Potential Role and Regulatory Mechanism in Host Immune Response in Diseases

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