Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India.
Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India.
Life Sci. 2020 Nov 15;261:118372. doi: 10.1016/j.lfs.2020.118372. Epub 2020 Aug 31.
Despite remarkable progress in understanding and treating oral cancer (OC), it still remains one of the life-threatening diseases and predominant cancers in the world. Therefore, deciphering the molecular mechanisms of this disease would help us to develop highly efficacious therapies. Multiple lines of evidence suggest that calcium and its dysregulation play significant role in the development of various cancers. As an adaptation of survival mechanism, upon depletion of ER calcium stores, store-operated calcium entry (SOCE) has been induced via SOCE channels (SOCC) in various mammalian cells. SOCC are regulated by Orai-1, Orai-2 and Orai-3 located on plasma membrane and two calcium-sensing ER membrane proteins known as stromal interaction molecules (STIM-1 and STIM-2). Hence, the present study was aimed at analysing the role of Orai-1 and Orai-2 in oral cancer and the underlying mechanism. Our results suggest that both Orai-1 and Orai-2 proteins were overexpressed in oral cancer tissues and cell lines (SAS) compared to normal epithelial tissues and cell lines respectively. In addition, silencing of Orai-1 and Orai-2 via chemical SOCE inhibitors and siRNAs inhibited calcium uptake and suppressed oral cancer cell proliferation, colony formation and migration. Furthermore, silencing of Orai-1 and Orai-2 inhibited Akt/mTOR/NF-κB pathway in oral cancer cells. Interestingly, tobacco carcinogen NNN and synthetic carcinogen 4-NQO, enhanced the expression of Orai-1 and Orai-2 in SAS cells. Therefore, we conclude that Orai-1 and Orai-2 have significant role in oral cancer and can be further explored to develop novel therapies for the treatment of this disease.
尽管人们在理解和治疗口腔癌 (OC) 方面取得了显著进展，但它仍然是世界上威胁生命的疾病和主要癌症之一。因此，破译这种疾病的分子机制将有助于我们开发高效的治疗方法。有多项证据表明，钙及其失调在各种癌症的发展中起着重要作用。作为生存机制的一种适应，在 ER 钙库耗竭后，各种哺乳动物细胞通过 SOCE 通道 (SOCC) 诱导了储存操作钙进入 (SOCE)。SOCC 受位于质膜上的 Orai-1、Orai-2 和 Orai-3 以及两种称为基质相互作用分子 (STIM-1 和 STIM-2) 的内质网钙感应蛋白调节。因此，本研究旨在分析 Orai-1 和 Orai-2 在口腔癌中的作用及其潜在机制。我们的研究结果表明，与正常上皮组织和细胞系相比，Orai-1 和 Orai-2 蛋白在口腔癌组织和细胞系 (SAS) 中均过度表达。此外，通过化学 SOCE 抑制剂和 siRNA 沉默 Orai-1 和 Orai-2 抑制了钙摄取并抑制了口腔癌细胞的增殖、集落形成和迁移。此外，沉默 Orai-1 和 Orai-2 抑制了口腔癌细胞中的 Akt/mTOR/NF-κB 通路。有趣的是，烟草致癌原 NNN 和合成致癌原 4-NQO 增强了 SAS 细胞中 Orai-1 和 Orai-2 的表达。因此，我们得出结论，Orai-1 和 Orai-2 在口腔癌中具有重要作用，可以进一步探索开发治疗这种疾病的新疗法。
