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

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....

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Autores principales: Jeon, Su-Jin, Ahn, Jun-Ho, Halder, Debasish, Cho, Hyun-Soo, Lim, Jung-Hwa, Jun, Soo Young, Lee, Jeong-Ju, Yoon, Ji-Yong, Choi, Min-Hyuk, Jung, Cho-Rok, Kim, Jin-Man, Kim, Nam-Soon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925247/
https://www.ncbi.nlm.nih.gov/pubmed/31862913
http://dx.doi.org/10.1038/s41419-019-2190-0
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author Jeon, Su-Jin
Ahn, Jun-Ho
Halder, Debasish
Cho, Hyun-Soo
Lim, Jung-Hwa
Jun, Soo Young
Lee, Jeong-Ju
Yoon, Ji-Yong
Choi, Min-Hyuk
Jung, Cho-Rok
Kim, Jin-Man
Kim, Nam-Soon
author_facet Jeon, Su-Jin
Ahn, Jun-Ho
Halder, Debasish
Cho, Hyun-Soo
Lim, Jung-Hwa
Jun, Soo Young
Lee, Jeong-Ju
Yoon, Ji-Yong
Choi, Min-Hyuk
Jung, Cho-Rok
Kim, Jin-Man
Kim, Nam-Soon
author_sort Jeon, Su-Jin
collection PubMed
description 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.
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spelling pubmed-69252472019-12-22 TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway Jeon, Su-Jin Ahn, Jun-Ho Halder, Debasish Cho, Hyun-Soo Lim, Jung-Hwa Jun, Soo Young Lee, Jeong-Ju Yoon, Ji-Yong Choi, Min-Hyuk Jung, Cho-Rok Kim, Jin-Man Kim, Nam-Soon Cell Death Dis Article 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. Nature Publishing Group UK 2019-12-20 /pmc/articles/PMC6925247/ /pubmed/31862913 http://dx.doi.org/10.1038/s41419-019-2190-0 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Jeon, Su-Jin
Ahn, Jun-Ho
Halder, Debasish
Cho, Hyun-Soo
Lim, Jung-Hwa
Jun, Soo Young
Lee, Jeong-Ju
Yoon, Ji-Yong
Choi, Min-Hyuk
Jung, Cho-Rok
Kim, Jin-Man
Kim, Nam-Soon
TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway
title TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway
title_full TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway
title_fullStr TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway
title_full_unstemmed TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway
title_short TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway
title_sort tiprl potentiates survival of lung cancer by inducing autophagy through the eif2α-atf4 pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925247/
https://www.ncbi.nlm.nih.gov/pubmed/31862913
http://dx.doi.org/10.1038/s41419-019-2190-0
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