ArticleCell death & disease2021
Downregulation of PHLPP induced by endoplasmic reticulum stress promotes eIF2α phosphorylation and chemoresistance in colon cancer.
Article in Cell death & disease, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 30 citations in OpenAlex.
- Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy.Signal transduction and targeted therapy · 2026Review
- Melatonin Induces PERK-ATF4 Unfolded Protein Response and Apoptosis in Human Choriocarcinoma Cells.Journal of pineal research · 2025Article
- Inhibition of anti-apoptotic Bcl-2 family members promotes synergistic cell death with ER stress inducers by disrupting autophagy in glioblastoma.Cell death discovery · 2025Article
- PHLPP and LAMP2 predict favorable treatment response and survival in multiple myeloma patients who receive induction treatment with bortezomib.Irish journal of medical science · 2025Article
- Identification and validation of endoplasmic reticulum stress-related genes that enhance immunotherapy in colon cancer.Translational cancer research · 2024Article
- Endoplasmic reticulum stress-a key guardian in cancer.Cell death discovery · 2024Review
- Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer.Molecular medicine (Cambridge, Mass.) · 2024Review
- SEC23A confers ER stress resistance in gastric cancer by forming the ER stress-SEC23A-autophagy negative feedback loop.Journal of experimental & clinical cancer research : CR · 2023Article
- An initial characterisation of the Unfolded Protein Response pathway in haematopoietic canine cancer cell lines - a necessary step for the future development of new therapies in dogs with neoplasia.Journal of veterinary research · 2023Article
- Characteristics of endoplasmic reticulum stress in colorectal cancer for predicting prognosis and developing treatment options.Cancer medicine · 2023Article
- Emerging roles of endoplasmic reticulum stress in the cellular plasticity of cancer cells.Frontiers in oncology · 2023Review
- Emerging roles of PHLPP phosphatases in lung cancer.Frontiers in oncology · 2023Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
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.
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