Orai3-Mediates Cisplatin-Resistance in Non-Small Cell Lung Cancer Cells by Enriching Cancer Stem Cell Population through PI3K/AKT Pathway

Abstract

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.

The tRNA-derived fragment 5026a inhibits the proliferation of gastric cancer cells by regulating the PTEN/PI3K/AKT signaling pathway

“…Guzzi et al found that in mammalian stem cells, post-transcriptional RNA modification affected the biogenesis and function of tRFs [ 43 ]. PTEN/PI3K/Akt pathway is related to CSCs in various cancers [ 44 – 46 ]. Dubrovska et al found that the PTEN/PI3K/Akt pathway was closely related to prostate CSCs and PI3K might be an effective therapeutic target of prostate cancer [ 45 ].…”

“…Dubrovska et al found that the PTEN/PI3K/Akt pathway was closely related to prostate CSCs and PI3K might be an effective therapeutic target of prostate cancer [ 45 ]. In non-small cell lung cancer (NSCLC), PI3K/AKT pathway plays a great role in the enrichment of CSCs, thereby promoting the occurrence and development of NSCLC [ 46 ]. And some small RNAs such as miR-873 inhibits the proliferation and differentiation of pancreatic CSCs mediated through PI3K/AKT signaling pathway [ 47 ].…”

Role of Orai3 in the Pathophysiology of Cancer

“…A recent study has reported that Orai3 induces cisplatin resistance in NSCLC cells by enriching the population of cancer stem cells [ 51 ]. Unlike Orai1, Orai3 expression is significantly enhanced in bronchial biopsies after treatment with cisplatin, which shifts the Orai1:Orai3 expression ratio in favor of Orai3, enhances SOCE, and is associated with the expression of cancer stem cells markers, Nanog and SOX-2, most likely mediated by a mechanism dependent on the activation of the PI3K/AKT pathway [ 51 ].…”

“…A recent study has reported that Orai3 induces cisplatin resistance in NSCLC cells by enriching the population of cancer stem cells [ 51 ]. Unlike Orai1, Orai3 expression is significantly enhanced in bronchial biopsies after treatment with cisplatin, which shifts the Orai1:Orai3 expression ratio in favor of Orai3, enhances SOCE, and is associated with the expression of cancer stem cells markers, Nanog and SOX-2, most likely mediated by a mechanism dependent on the activation of the PI3K/AKT pathway [ 51 ]. Interestingly, this study also reveals that the activation of the PI3K/AKT pathway is essential for the increase in Orai3 expression after treatment with cisplatin [ 51 ], which suggest a positive feedback mechanism in the regulation of Orai3 expression and PI3K/AKT activation upon treatment with cisplatin and reveals that Orai3 might be a useful target to monitor the lung cancer outcome upon the treatment with chemotherapeutic drugs.…”

Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

“…It is well reported that 2APB in the same concentration range of 30-50µM blocks Orai1 and activates Orai3 channels [36][37][38][39]. In past, several groups have used 2APB (50µM) to demonstrate Orai3 activation as a functional SOCE channel in breast and lung cancers [20,23,24,40,41]. Therefore, in order to examine the functionality of Orai3 as a SOCE channel in pancreatic cells, we used 2APB (50µM) in our live cell Ca 2+ imaging experiments.…”