Genome Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea.
Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, Republic of Korea.
Cell Death Dis. 2019 Dec 20;10(12):959. doi: 10.1038/s41419-019-2190-0.
Autophagy, an intracellular system of degrading damaged organelles and misfolded proteins, is essential for cancer cell survival. Despite the progress made towards understanding the mechanism, identification of novel autophagy regulators presents a major obstacle in developing anticancer therapies. Here, we examine the association between the TOR signaling pathway regulator-like (TIPRL) protein and autophagy in malignant transformation of tumors. We show that TIPRL upregulation in non-small cell lung cancer (NSCLC) potentiated autophagy activity and enabled autophagic clearance of metabolic and cellular stress, conferring a survival advantage to cancer cells. Importantly, the interaction of TIPRL with eukaryotic initiation factor 2α (eIF2α) led to eIF2α phosphorylation and activation of the eIF2α-ATF4 pathway, thereby inducing autophagy. Conversely, TIPRL depletion increased apoptosis by reducing autophagic clearance, which was markedly enhanced in TIPRL-depleted A549 xenografts treated with 2-deoxy-D-glucose. Overall, the study indicated that TIPRL is a potential regulator of autophagy and an important drug target for lung cancer therapy.
自噬是一种降解受损细胞器和错误折叠蛋白质的细胞内系统，对癌细胞的存活至关重要。尽管在理解其机制方面取得了进展，但鉴定新的自噬调节剂仍然是开发抗癌疗法的主要障碍。在这里，我们研究了 TOR 信号通路调节剂样（TIPRL）蛋白与肿瘤恶性转化过程中的自噬之间的关联。我们发现，非小细胞肺癌（NSCLC）中 TIPRL 的上调增强了自噬活性，并使代谢和细胞应激的自噬清除成为可能，从而为癌细胞提供了生存优势。重要的是，TIPRL 与真核起始因子 2α（eIF2α）的相互作用导致 eIF2α 的磷酸化和 eIF2α-ATF4 途径的激活，从而诱导自噬。相反，TIPRL 的耗竭通过减少自噬清除来增加细胞凋亡，在用 2-脱氧-D-葡萄糖处理的 TIPRL 耗竭的 A549 异种移植物中，这种作用明显增强。总的来说，该研究表明 TIPRL 是自噬的潜在调节剂，也是肺癌治疗的一个重要药物靶点。
