Abstract
Simple SummaryLung cancer is recognized for having a very poor prognosis with an overall survival rate of 5-years not exceeding 15%. Platinum-doublet therapy is the most current chemotherapeutic treatment used to treat lung tumors. However, resistance to such drugs evolves rapidly in patients with non-small cell lung cancer (NSCLC) and is one of the major reasons behind therapy failure. Tumor recurrence due to chemoresistance is mainly attributed to the presence of cancer stem cells (CSCs) subpopulations. Thus, the identification of resistance actors and markers is necessary. The Orai3 channel has been recently identified as a predictive marker of metastasis and survival in resectable NSCLC tumors. Our results show, for the first time, that the Orai3 channel is able to induce chemoresistance by enriching CSCs population. Our findings present Orai3 as a promising predictive biomarker which could help with selecting chemotherapeutic drugs.The development of the resistance to platinum salts is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). Among the reasons underlying this resistance is the enrichment of cancer stem cells (CSCs) populations. Several studies have reported the involvement of calcium channels in chemoresistance. The Orai3 channel is overexpressed and constitutes a predictive marker of metastasis in NSCLC tumors. Here, we investigated its role in CSCs populations induced by Cisplatin (CDDP) in two NSCLC cell lines. We found that CDDP treatment increased Orai3 expression, but not Orai1 or STIM1 expression, as well as an enhancement of CSCs markers. Moreover, Orai3 silencing or the reduction of extracellular calcium concentration sensitized the cells to CDDP and led to a reduction in the expression of Nanog and SOX-2. Orai3 contributed to SOCE (Store-operated Calcium entry) in both CDDP-treated and CD133+ subpopulation cells that overexpress Nanog and SOX-2. Interestingly, the ectopic overexpression of Orai3, in the two NSCLC cell lines, lead to an increase of SOCE and expression of CSCs markers. Furthermore, CD133+ cells were unable to overexpress neither Nanog nor SOX-2 when incubated with PI3K inhibitor. Finally, Orai3 silencing reduced Akt phosphorylation. Our work reveals a link between Orai3, CSCs and resistance to CDDP in NSCLC cells.
Highlights
Lung cancer continues to be the deadliest cancer worldwide and the most frequently diagnosed cancer type in both sexes [1]
The staining score of Orai3 increased by 310.2% (Figure 1c, 0.39 ± 0.31 vs. 1.21 ± 0.79; p < 0.05, Mann–Whitney U test) and the one of Orai1 decreased by 33.8% (Figure 1c, 1.33 ± 0.46 vs. 0.88 ± 0.48 p < 0.05, Mann–Whitney U test)
As CDDP induced an overexpression of Orai3, and as Orai3 favors the survival of cells treated with CDDP, we investigated the effect of Orai3 overexpression on apoptosis resistance in A549 cells under normal culture conditions and in the presence of CDDP
Summary
Lung cancer continues to be the deadliest cancer worldwide and the most frequently diagnosed cancer type in both sexes [1]. Among the different histological types of lung cancer, non-small cell lung cancer (NSCLC) comprises the majority of cases (about 85%) including adenocarcinomas, squamous cell carcinomas, and large cell carcinomas [2]. The severity of this type relies notably on the late diagnosis which hinders the surgical operation and restricts the treatments to radiotherapy and chemotherapy. CDDP-based chemotherapy regimens proved to increase the average survival in patients with NSCLC [3]. Statistics reveal that up to 43% of NSCLC patients endure tumor recurrence due to chemoresistance [6]
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