IMPA2 blocks cervical cancer cell apoptosis and induces paclitaxel resistance through p53-mediated AIFM2 regulation
Kexin Xie, Lei Liu, Min Wang, Xianping Li, Bingqi Wang, Sheng Yin, Wanxin Chen, Yingrui Lin, Xiaolin Zhu
Abstract
<p indent="0mm">Cervical cancer continues to be a concern, and the prognosis of locally advanced cervical cancer remains poor. <italic>IMPA2</italic> was previously identified as a potential oncogene and regulator of tumor apoptosis. In this study, we aim to further elucidate the underlying mechanisms of <italic>IMPA2</italic> gene in the regulation of cervical cancer apoptosis. First, we identify <italic>AIFM2</italic> as an upregulated gene in <italic>IMPA2</italic>-silenced cervical cancer cells, and inhibition of <italic>AIFM2</italic> reverses <italic>IMPA2</italic> knockdown-induced apoptosis. Further study reveals that <italic>AIFM2</italic> regulates cell apoptosis in a mitochondrial-dependent manner with a redistribution of mitochondrial membrane potential and intracellular Ca <sup>2+</sup> levels. However, the analysis of the STRING database and our experimental results show that <italic>AIFM2</italic> has little effect on cervical cancer progression and survival. Further mechanistic study demonstrates that <italic>IMPA2</italic> and <italic>AIFM2</italic> silencing inhibits apoptosis by activating p53. Meanwhile, the knockdown of <italic>IMPA2</italic> enhances the chemosensitivity of cervical cancer cells by strengthening paclitaxel-induced apoptosis. Based on the above results, the IMPA2/AIFM2/p53 pathway may be a new molecular mechanism for paclitaxel treatment of cervical cancer and an effective strategy to enhance the sensitivity of cervical cancer cells to paclitaxel. Our findings display a novel function of <italic>IMPA2</italic> in regulating cell apoptosis and paclitaxel resistance mediated by a disturbance of <italic>AIFM2</italic> and <italic>p53</italic> expression, potentially making it a novel therapeutic target for cervical cancer treatment.