School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
Mechanobiology Institute, Singapore 117411, Singapore.
Cell Death Dis. 2017 Sep 14;8(9):e3051. doi: 10.1038/cddis.2017.443.
Chemoresistance is one of the leading causes that contributes to tumor relapse and poor patient outcome after several rounds of drug therapy. The causes of chemoresistance are multi-factorial. Ultimately, it is the balance of pro- and anti-apoptotic activities in the cells. We have previously reported links between POPX2 serine/threonine phosphatase with cell motility and invasiveness of breast cancer cells. Here, we show that POPX2 plays a role in the regulation of apoptosis. The effect of POPX2 on apoptosis centers on the inactivation of TGF-β activated kinase (TAK1). TAK1 is essential for several important biological functions including innate immunity, development and cell survival. We find that POPX2 interacts directly with TAK1 and is able to dephosphorylate TAK1. Cells with lower levels of POPX2 exhibit higher TAK1 activity in response to etoposide (VP-16) treatment. This subsequently leads to increased translocation of NF-κB from the cytosol to the nucleus. Consequently, NF-κB-mediated transcription of anti-apoptotic proteins is upregulated to promote cell survival. On the other hand, cells with higher levels of POPX2 are more vulnerable to apoptosis induced by etoposide. Our data demonstrate that POPX2 is a negative regulator of TAK1 signaling pathway and modulates apoptosis through the regulation of TAK1 activity. As inhibition of TAK1 has been proposed to reduce chemoresistance and increase sensitivity to chemotherapy in certain types of cancer, modulation of POPX2 levels may provide an additional avenue and consideration in fine-tuning therapeutic response.
化学耐药性是导致肿瘤复发和多次药物治疗后患者预后不良的主要原因之一。化学耐药性的原因是多因素的。最终，这是细胞中促凋亡和抗凋亡活性的平衡。我们之前曾报道过 POPX2 丝氨酸/苏氨酸磷酸酶与乳腺癌细胞的细胞迁移和侵袭之间的联系。在这里，我们表明 POPX2 在细胞凋亡的调节中起作用。POPX2 对细胞凋亡的影响主要集中在 TGF-β激活激酶 (TAK1) 的失活上。TAK1 对包括先天免疫、发育和细胞存活在内的几个重要生物学功能是必不可少的。我们发现 POPX2 与 TAK1 直接相互作用，并能够使 TAK1 去磷酸化。在伊立替康（VP-16）治疗下，POPX2 水平较低的细胞表现出更高的 TAK1 活性。这随后导致 NF-κB 从细胞质易位到细胞核。结果，NF-κB 介导的抗凋亡蛋白的转录被上调以促进细胞存活。另一方面，POPX2 水平较高的细胞对伊立替康诱导的细胞凋亡更敏感。我们的数据表明，POPX2 是 TAK1 信号通路的负调节剂，并通过调节 TAK1 活性来调节细胞凋亡。由于抑制 TAK1 已被提议减少某些类型癌症的化学耐药性并增加对化疗的敏感性，因此调节 POPX2 水平可能为精细调节治疗反应提供了另一种途径和考虑因素。
