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TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway

Authors :
Jeong-Ju Lee
Min-Hyuk Choi
Debasish Halder
Cho-Rok Jung
Jung-Hwa Lim
Su-Jin Jeon
Jun-Ho Ahn
Nam-Soon Kim
Ji-Yong Yoon
Soo Young Jun
Jin-Man Kim
Hyun-Soo Cho
Source :
Cell Death & Disease, Cell Death and Disease, Vol 10, Iss 12, Pp 1-17 (2019)
Publication Year :
2019
Publisher :
Springer Science and Business Media LLC, 2019.

Abstract

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.

Details

ISSN :
20414889
Volume :
10
Database :
OpenAIRE
Journal :
Cell Death & Disease
Accession number :
edsair.doi.dedup.....00cb0e5179a2d3cdef3662f6d69d1be8
Full Text :
https://doi.org/10.1038/s41419-019-2190-0