Intracellular calcium promotes radioresistance of non–small cell lung cancer A549 cells through activating Akt signaling

Wang, Yiling; He, Jiantao; Zhang, Shenghui; Yang, Qingbo

doi:10.1177/1010428317695970

Cited by 7 publications

(5 citation statements)

References 13 publications

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“…There are studies supporting our results, showing that high intracellular Ca 2+ levels decrease Akt phosphorylation and that buffering intracellular Ca 2+ can increase Akt phosphorylation (Conus et al , 1998; Kang et al , 2017). Conversely, other studies claim that increased intracellular Ca 2+ promotes Akt activity (Divolis et al , 2016; Wang et al , 2017). Certainly, there are underlying mechanisms in the regulation of Akt that remain incompletely understood and that require further studies in the future.…”

Section: Discussionmentioning

confidence: 93%

Neuronal Calcium Sensor 1 is up‐regulated in response to stress to promote cell survival and motility in cancer cells

et al. 2020

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Changes in intracellular calcium (Ca 2+ ) signaling can modulate cellular machinery required for cancer progression. Neuronal calcium sensor 1 (NCS1) is a ubiquitously expressed Ca 2+ -binding protein that promotes tumor aggressiveness by enhancing cell survival and metastasis. However, the underlying mechanism by which NCS1 contributes to increased tumor aggressiveness has yet to be identified. In this study, we aimed to determine (a) whether NCS1 expression changes in response to external stimuli, (b) the importance of NCS1 for cell survival and migration, and (c) the cellular mechanism(s) through which NSC1 modulates these outcomes. We found that NCS1 abundance increases under conditions of stress, most prominently after stimulation with the pro-inflammatory cytokine tumor necrosis factor a, in a manner dependent on nuclear factor kappa-light-chain-enhancer of activated B cells (NFjB). We found that NFjB signaling is activated in human breast cancer tissue, which was accompanied by an increase in NCS1 mRNA expression. Further exploration into the relevance of NCS1 in breast cancer progression showed that knockout of NCS1 (NCS1 KO) caused decreased cell survival and motility, increased baseline intracellular Ca 2+ levels, and decreased inositol 1,4,5-trisphosphate-mediated Ca 2+ responses. Protein kinase B (Akt) activity was decreased in NCS1 KO cells, which could be rescued by buffering intracellular Ca 2+ . Conversely, Akt activity was increased in cells overexpressing NCS1 (NCS1 OE). We therefore conclude that NCS1 acts as cellular stress response protein up-regulated by stress-induced NFjB signaling and that NCS1 influences cell survival and motility through effects on Ca 2+ signaling and Akt pathway activation. AbbreviationsAkt, protein kinase B; Ca 2+ , calcium; ER, endoplasmic reticulum; InsP3, inositol 1,4,5-trisphosphate; InsP3R, inositol 1,4,5-trisphosphate receptor; IjBa, nuclear factor of kappa-light polypeptide gene enhancer in B-cell inhibition, alpha; NCS1, neuronal calcium sensor 1; NFjB, nuclear factor kappa-light-chain-enhancer of activated B cells; p-Akt, phosphorylated Akt; PI3K, phosphoinositide-3-kinase; PP2Ac, catalytic subunit of protein phosphatase 2A; tBHP, tert-butylhydroperoxide; TG, thapsigargin; TNF-a, tumor necrosis factor alpha.

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Section: Discussionmentioning

confidence: 93%

Neuronal Calcium Sensor 1 is up‐regulated in response to stress to promote cell survival and motility in cancer cells

et al. 2020

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“…This result was shown in another study in which the researchers analyzed the expression of FRa in 27 lung cancer cell lines, including 19 LUAD, 1 lung squamous cell carcinoma (SqCC), 1 lung adenosquamous carcinoma (ASC), 3 small cell lung cancer (SCLC) and 3 lung large cell carcinoma (LCC) cell lines, and only observed strong bands in the Western blots of A549 (LUAD), H647 (ASC), H460 (LCC) and SBC-5, KB (SCLC) cell lines, whereas other cell lines had faint or no bands, especially LUAD cell lines (24). Given the importance of pemetrexed in the clinical treatment of LUAD and the similar expression level of FRa to human LUAD, we constructed an A549 radioresistant cell model to study changes in the sensitivity of radioresistant cells to pemetrexed, which has been widely used in other studies to illustrate the internal mechanisms of acquired radioresistance (29,30). Radioresistant isogenic cell models have been generated for many human cancer lines and have formed the basis for the identification of mechanisms of radioresistance (31,32).…”

Section: Discussionmentioning

confidence: 99%

Decitabine Sensitizes the Radioresistant Lung Adenocarcinoma to Pemetrexed Through Upregulation of Folate Receptor Alpha

Wang

Huang

et al. 2021

Front. Oncol.

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Chemotherapy is the backbone of subsequent treatment for patients with lung adenocarcinoma (LUAD) exhibiting radiation resistance, and pemetrexed plays a critical role in this chemotherapy. However, few studies have assessed changes in the sensitivity of LUAD cells to pemetrexed under radioresistant circumstances. Therefore, the objectives of this study were to delineate changes in the sensitivity of radioresistant LUAD cells to pemetrexed and to elucidate the related mechanisms and then develop an optimal strategy to improve the cytotoxicity of pemetrexed in radioresistant LUAD cells. Our study showed a much lower efficacy of pemetrexed in radioresistant cells than in parental cells, and the mechanism of action was the significant downregulation of folate receptor alpha (FRα) by long-term fractionated radiotherapy, which resulted in less cellular pemetrexed accumulation. Interestingly, decitabine effectively reversed the decrease in FRα expression in radioresistant cells through an indirect regulatory approach. Thereafter, we designed a combination therapy of pemetrexed and decitabine and showed that the activation of FRα by decitabine sensitizes radioresistant LUAD cells to pemetrexed both in vitro and in xenografts. Our findings raised a question regarding the administration of pemetrexed to patients with LUAD exhibiting acquired radioresistance and accordingly suggested that a combination of pemetrexed and decitabine would be a promising treatment strategy.

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“…Radioresistant cell lines can be established via cumulative exposure to irradiation [25][26][27]. In our study, the radioresistant cell line CNE-2R was successfully obtained using a gradient irradiation schedule with accumulated doses of 60 Gy.…”

Section: Discussionmentioning

confidence: 99%

Discrepant expression and prognostic role of epidermal growth factor receptor and icotinib radiosensitization for nasopharyngeal carcinoma

Xiong

Wang

et al. 2020

Preprint

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Background: Epidermal growth factor receptor (EGFR) expression was observed in many tumors. Icotinib (IH), an EGFR tyrosine kinase inhibitor, could enhance the radiosensitivity, but few studies have focused on nasopharyngeal carcinoma (NPC). Materials and Methods : One hundred fifteen NPC lesions and 30 nasopharyngitis lesions were enrolled for EGFR expression evaluation with immunohistochemical staining. The correlation of EGFR expression and clinical parameters was analyzed. Survival analysis was calculated using univariate and multivariate analysis. A radioresistant NPC cell line, CNE-2R, was established with a gradient irradiation schedule of 60 Gy from CNE-2. Cell viability of CNE-2/2R was detected using microculture tetrazolium assay and colony-forming assay. The IH radiosensitization effect and EGFR expression were also evaluated in CNE-2/2R. Results: High EGFR expression was more frequently detected in NPC lesions (73/115) than chronic nasopharyngitis lesions (5/30, p =0.000). EGFR expression was correlated with tumor stage ( p =0.000) and tumor-node-metastasis (TNM) stage ( p =0.006). EGFR expression was an independent prognostic factor of disease-free survival ( p =0.047) and overall survival ( p =0.016). The optical density value of CNE-2R was higher than CNE-2 on days 1, 2, 4, and 6 after radiation of 4 Gy ( p <0.005). CNE-2 colony numbers clearly decreased compared with CNE-2R ( p <0.05), and IH enhanced the radiosensitizing effect of CNE-2R with an apparently lower survival fraction (1.414 times, p <0.05). Higher EGFR expression was observed in CNE-2R cells and decreased accordingly when exposed to IH. Conclusion: High EGFR expression was more frequently detected as a poor prognostic factor in NPC patients. Higher radioresistance and EGFR expression were observed in CNE-2R, and IH could reduce it. These results provided a new theoretical basis for clinical application of icotinib radiosensitization in NPC radiotherapy.

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Intracellular calcium promotes radioresistance of non–small cell lung cancer A549 cells through activating Akt signaling

Cited by 7 publications

References 13 publications

Neuronal Calcium Sensor 1 is up‐regulated in response to stress to promote cell survival and motility in cancer cells

Neuronal Calcium Sensor 1 is up‐regulated in response to stress to promote cell survival and motility in cancer cells

Decitabine Sensitizes the Radioresistant Lung Adenocarcinoma to Pemetrexed Through Upregulation of Folate Receptor Alpha

Discrepant expression and prognostic role of epidermal growth factor receptor and icotinib radiosensitization for nasopharyngeal carcinoma

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