Institute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.
Department of Urology, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China.
Int J Med Sci. 2020 Jun 29;17(11):1652-1664. doi: 10.7150/ijms.46034. eCollection 2020.
Cancer cells can enter quiescent or dormant state to resist anticancer agents while maintaining the potential of reactivation. However, the molecular mechanism underlying quiescence entry and reactivation remains largely unknown. In this paper, cancer cells eventually entered a reversible quiescent state to resist long-term paclitaxel (PTX) stress. The quiescent cells were characterized with Na/H exchanger 1 (NHE1) downregulation and showed acidic intracellular pH (pH). Accordingly, decreasing pH by NHE1 inhibitor could induce cell enter quiescence. Further, acidic pH could activate the ubiquitin-proteasome system and inhibiting proteasome activity by MG132 prevented cells entering quiescence. In addition, we show that after partial release, the key G1-S transcription factor E2F1 protein level was not recovered, while MCM7 protein returned to normal level in the reactivated cells. More importantly, MCM7 knockdown inhibited G1/S genes transcription and inhibited the reactivated proliferation. Taken together, this study demonstrates a regulatory function of intracellular acidification and subsequent protein ubiquitination on quiescence entry, and reveals a supportive effect of MCM7 on the quiescence-reactivated proliferation.
癌细胞可以进入静止或休眠状态，以抵抗抗癌药物，同时保持重新激活的潜力。然而，静止进入和重新激活的分子机制在很大程度上仍然未知。在本文中，癌细胞最终进入了一种可逆的静止状态，以抵抗长期紫杉醇（PTX）的压力。静止细胞的特征是 Na/H 交换器 1（NHE1）下调，并显示出酸性细胞内 pH（pH）。因此，通过 NHE1 抑制剂降低 pH 值可以诱导细胞进入静止状态。此外，酸性 pH 值可以激活泛素-蛋白酶体系统，而用 MG132 抑制蛋白酶体活性可以防止细胞进入静止状态。此外，我们还表明，在部分释放后，关键的 G1-S 转录因子 E2F1 蛋白水平没有恢复，而在重新激活的细胞中，MCM7 蛋白恢复到正常水平。更重要的是，MCM7 敲低抑制了 G1/S 基因的转录，并抑制了重新激活的增殖。总之，这项研究表明细胞内酸化和随后的蛋白质泛素化对静止进入具有调节功能，并揭示了 MCM7 对静止-重新激活增殖的支持作用。
