Gualdani Roberta, de Clippele Marie, Ratbi Ikram, Gailly Philippe, Tajeddine Nicolas
Laboratory of Cell Physiology, Institute of Neuroscience, Université Catholique de Louvain, Brussels 1200, Belgium.
Cancers (Basel). 2019 Mar 26;11(3):430. doi: 10.3390/cancers11030430.
Cisplatin (CDDP) is one of the principal chemotherapeutic agents used for the first-line treatment of many malignancies, including non-small cell lung carcinoma (NSCLC). Despite its use for over 40 years, its mechanism of action is not yet fully understood. Store-operated calcium entry (SOCE), the main pathway allowing Ca entry in non-excitable cells, is involved in tumorogenesis, cancer progression and chemoresistance. It has become an attractive target in cancer treatment. In this study, we showed that siRNA-mediated depletion of stromal interaction molecule 1 (STIM1) and transient receptor potential channel 1 (TRPC1), two players of the store-operated calcium entry, dramatically reduced CDDP cytotoxicity in NSCLC cells. This was associated with an inhibition of the DNA damage response (DDR) triggered by CDDP. Moreover, STIM1 depletion also reduced CDDP-dependent oxidative stress. In parallel, SOCE activation induced Ca entry into the mitochondria, a major source of reactive oxygen species (ROS) within the cell. This effect was highly decreased in STIM1-depleted cells. We then conclude that mitochondrial Ca peak associated to the SOCE contributes to CDDP-induced ROS production, DDR and subsequent apoptosis. To the best of our knowledge, this is the first time that it is shown that Ca signalling constitutes an initial step in CDDP-induced apoptosis.
顺铂（CDDP）是用于多种恶性肿瘤一线治疗的主要化疗药物之一，包括非小细胞肺癌（NSCLC）。尽管其已使用40多年，但其作用机制尚未完全明确。储存式钙内流（SOCE）是允许Ca进入非兴奋性细胞的主要途径，参与肿瘤发生、癌症进展和化疗耐药。它已成为癌症治疗中一个有吸引力的靶点。在本研究中，我们表明siRNA介导的基质相互作用分子1（STIM1）和瞬时受体电位通道1（TRPC1）（储存式钙内流的两个参与者）的缺失显著降低了NSCLC细胞中CDDP的细胞毒性。这与抑制CDDP触发的DNA损伤反应（DDR）有关。此外，STIM1的缺失还降低了CDDP依赖性氧化应激。同时，SOCE激活诱导Ca进入线粒体，线粒体是细胞内活性氧（ROS）主要来源。在STIM1缺失的细胞中这种效应显著降低。我们进而得出结论，与SOCE相关的线粒体Ca峰有助于CDDP诱导的ROS产生、DDR及随后的细胞凋亡。据我们所知，这是首次表明Ca信号传导是CDDP诱导细胞凋亡的起始步骤。
