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

被引:12
|
作者
Guo, Bianqin [1 ]
Xiong, Xiaopeng [2 ]
Hasani, Sumati [2 ,3 ]
Wen, Yang-An [2 ]
Li, Austin T. [4 ,6 ]
Martinez, Rebecca [5 ]
Skaggs, Ashley T. [2 ,3 ]
Gao, Tianyan [2 ,3 ]
机构
[1] Chongqing Univ, Chongqing Key Lab Translat Res Canc Metastasis &, Canc Hosp, Chongqing 400030, Peoples R China
[2] Univ Kentucky, Markey Canc Ctr, Lexington, KY 40506 USA
[3] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40506 USA
[4] Paul Laurence Dunbar High Sch, Lexington, KY USA
[5] Univ Kentucky, Coll Agr Food & Environm, Agr & Med Biotechnol Program, Lexington, KY USA
[6] Princeton Univ, Princeton, NJ 08544 USA
基金
美国国家科学基金会;
关键词
CELL MOTILITY; PHOSPHATASE; EXPRESSION; AKT; TRANSLATION; INHIBITION; RESISTANCE; SURVIVAL; CREP;
D O I
10.1038/s41419-021-04251-0
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 eIF2 alpha as well as the expression of autophagy-associated genes downstream of the eIF2 alpha/ATF4 signaling pathway. In addition, results from immunoprecipitation experiments showed that PHLPP interacted with eIF2 alpha 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 eIF2 alpha/ATF4 signaling axis in colon cancer cells.
引用
收藏
页数:9
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