Downregulation of PHLPP induced by endoplasmic reticulum stress promotes eIF2α phosphorylation and chemoresistance in colon cancer

Bianqin Guo; Xiaopeng Xiong; Sumati Hasani; Yang An Wen; Austin T. Li; Rebecca Martinez; Ashley T. Skaggs; Tianyan Gao

doi:10.1038/s41419-021-04251-0

Downregulation of PHLPP induced by endoplasmic reticulum stress promotes eIF2α phosphorylation and chemoresistance in colon cancer

Bianqin Guo, Xiaopeng Xiong, Sumati Hasani, Yang An Wen, Austin T. Li, Rebecca Martinez, Ashley T. Skaggs, Tianyan Gao

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

Aberrant activation of endoplasmic reticulum (ER) stress by extrinsic and intrinsic factors contributes to tumorigenesis and resistance to chemotherapies in various cancer types. Our previous studies have shown that the downregulation of PHLPP, a novel family of Ser/Thr protein phosphatases, promotes tumor initiation, and progression. Here we investigated the functional interaction between the ER stress and PHLPP expression in colon cancer. We found that induction of ER stress significantly decreased the expression of PHLPP proteins through a proteasome-dependent mechanism. Knockdown of PHLPP increased the phosphorylation of eIF2α as well as the expression of autophagy-associated genes downstream of the eIF2α/ATF4 signaling pathway. In addition, results from immunoprecipitation experiments showed that PHLPP interacted with eIF2α and this interaction was enhanced by ER stress. Functionally, knockdown of PHLPP improved cell survival under ER stress conditions, whereas overexpression of a degradation-resistant mutant PHLPP1 had the opposite effect. Taken together, our studies identified ER stress as a novel mechanism that triggers PHLPP downregulation; and PHLPP-loss promotes chemoresistance by upregulating the eIF2α/ATF4 signaling axis in colon cancer cells.

Original language	English
Article number	960
Journal	Cell Death and Disease
Volume	12
Issue number	11
DOIs	https://doi.org/10.1038/s41419-021-04251-0
State	Published - Nov 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Funding

This work was supported by R01CA133429 (TG). BG was supported by funding from Chongqing Science and Technology Commission (cstc2020jcyj-msxmX0907). ATS was supported by the National Science Foundation Graduate Research Fellowship Award (#1839289). SH was supported by NRSA F31CA260840 predoctoral fellowship. The studies were conducted with support provided by the Biostatistics and Bioinfor-matics, Biospecimen Procurement and Translational Pathology, Flow Cytometry and Immune Monitoring, and Redox Metabolism Shared Resource Facilities of the University of Kentucky Markey Cancer Center (P30CA177558). The summary diagram was created with BioRender.com.

Funders	Funder number
National Childhood Cancer Registry – National Cancer Institute	F31CA260840, R01CA133429
National Cancer Institute Division of Cancer Epidemiology and Genetics	P30CA177558
U.S. Department of Energy Chinese Academy of Sciences Guangzhou Municipal Science and Technology Project Oak Ridge National Laboratory Extreme Science and Engineering Discovery Environment National Science Foundation National Energy Research Scientific Computing Center National Natural Science Foundation of China	1839289
Chongqing Science and Technology Commission	cstc2020jcyj-msxmX0907
Israel National Road Safety Authority	F31CA260840

ASJC Scopus subject areas

Immunology
Cellular and Molecular Neuroscience
Cell Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41419-021-04251-0

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title = "Downregulation of PHLPP induced by endoplasmic reticulum stress promotes eIF2α phosphorylation and chemoresistance in colon cancer",

abstract = "Aberrant activation of endoplasmic reticulum (ER) stress by extrinsic and intrinsic factors contributes to tumorigenesis and resistance to chemotherapies in various cancer types. Our previous studies have shown that the downregulation of PHLPP, a novel family of Ser/Thr protein phosphatases, promotes tumor initiation, and progression. Here we investigated the functional interaction between the ER stress and PHLPP expression in colon cancer. We found that induction of ER stress significantly decreased the expression of PHLPP proteins through a proteasome-dependent mechanism. Knockdown of PHLPP increased the phosphorylation of eIF2α as well as the expression of autophagy-associated genes downstream of the eIF2α/ATF4 signaling pathway. In addition, results from immunoprecipitation experiments showed that PHLPP interacted with eIF2α and this interaction was enhanced by ER stress. Functionally, knockdown of PHLPP improved cell survival under ER stress conditions, whereas overexpression of a degradation-resistant mutant PHLPP1 had the opposite effect. Taken together, our studies identified ER stress as a novel mechanism that triggers PHLPP downregulation; and PHLPP-loss promotes chemoresistance by upregulating the eIF2α/ATF4 signaling axis in colon cancer cells.",

author = "Bianqin Guo and Xiaopeng Xiong and Sumati Hasani and Wen, \{Yang An\} and Li, \{Austin T.\} and Rebecca Martinez and Skaggs, \{Ashley T.\} and Tianyan Gao",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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AU - Guo, Bianqin

AU - Xiong, Xiaopeng

AU - Hasani, Sumati

AU - Wen, Yang An

AU - Li, Austin T.

AU - Martinez, Rebecca

AU - Skaggs, Ashley T.

AU - Gao, Tianyan

PY - 2021/11

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N2 - Aberrant activation of endoplasmic reticulum (ER) stress by extrinsic and intrinsic factors contributes to tumorigenesis and resistance to chemotherapies in various cancer types. Our previous studies have shown that the downregulation of PHLPP, a novel family of Ser/Thr protein phosphatases, promotes tumor initiation, and progression. Here we investigated the functional interaction between the ER stress and PHLPP expression in colon cancer. We found that induction of ER stress significantly decreased the expression of PHLPP proteins through a proteasome-dependent mechanism. Knockdown of PHLPP increased the phosphorylation of eIF2α as well as the expression of autophagy-associated genes downstream of the eIF2α/ATF4 signaling pathway. In addition, results from immunoprecipitation experiments showed that PHLPP interacted with eIF2α and this interaction was enhanced by ER stress. Functionally, knockdown of PHLPP improved cell survival under ER stress conditions, whereas overexpression of a degradation-resistant mutant PHLPP1 had the opposite effect. Taken together, our studies identified ER stress as a novel mechanism that triggers PHLPP downregulation; and PHLPP-loss promotes chemoresistance by upregulating the eIF2α/ATF4 signaling axis in colon cancer cells.

AB - Aberrant activation of endoplasmic reticulum (ER) stress by extrinsic and intrinsic factors contributes to tumorigenesis and resistance to chemotherapies in various cancer types. Our previous studies have shown that the downregulation of PHLPP, a novel family of Ser/Thr protein phosphatases, promotes tumor initiation, and progression. Here we investigated the functional interaction between the ER stress and PHLPP expression in colon cancer. We found that induction of ER stress significantly decreased the expression of PHLPP proteins through a proteasome-dependent mechanism. Knockdown of PHLPP increased the phosphorylation of eIF2α as well as the expression of autophagy-associated genes downstream of the eIF2α/ATF4 signaling pathway. In addition, results from immunoprecipitation experiments showed that PHLPP interacted with eIF2α and this interaction was enhanced by ER stress. Functionally, knockdown of PHLPP improved cell survival under ER stress conditions, whereas overexpression of a degradation-resistant mutant PHLPP1 had the opposite effect. Taken together, our studies identified ER stress as a novel mechanism that triggers PHLPP downregulation; and PHLPP-loss promotes chemoresistance by upregulating the eIF2α/ATF4 signaling axis in colon cancer cells.

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Downregulation of PHLPP induced by endoplasmic reticulum stress promotes eIF2α phosphorylation and chemoresistance in colon cancer

Abstract

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ASJC Scopus subject areas

UN SDGs

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