Loss of STIM2 in colorectal cancer drives growth and metastasis through metabolic reprogramming and PERK-ATF4 endoplasmic reticulum stress pathway.

Autor:	Pathak T; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States., Benson JC; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.; UPMC Hillman Cancer Center. University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States., Johnson MT; Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States., Xin P; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States., Abdelnaby AE; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States., Walter V; Department of Public Health Sciences, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States.; Penn State Cancer Institute. The Pennsylvania State University College of Medicine, Hershey, United States., Koltun WA; Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University College of Medicine, Hershey, United States., Yochum GS; Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, United States.; Department of Surgery, Division of Colon and Rectal Surgery, The Pennsylvania State University College of Medicine, Hershey, United States., Hempel N; UPMC Hillman Cancer Center. University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States., Trebak M; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.; UPMC Hillman Cancer Center. University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 03. Date of Electronic Publication: 2023 Oct 03.
DOI:	10.1101/2023.10.02.560521
Abstrakt:	The endoplasmic reticulum (ER) stores large amounts of calcium (Ca 2+ ), and the controlled release of ER Ca 2+ regulates a myriad of cellular functions. Although altered ER Ca 2+ homeostasis is known to induce ER stress, the mechanisms by which ER Ca 2+ imbalance activate ER stress pathways are poorly understood. Stromal-interacting molecules STIM1 and STIM2 are two structurally homologous ER-resident Ca 2+ sensors that synergistically regulate Ca 2+ influx into the cytosol through Orai Ca 2+ channels for subsequent signaling to transcription and ER Ca 2+ refilling. Here, we demonstrate that reduced STIM2, but not STIM1, in colorectal cancer (CRC) is associated with poor patient prognosis. Loss of STIM2 causes SERCA2-dependent increase in ER Ca 2+ , increased protein translation and transcriptional and metabolic rewiring supporting increased tumor size, invasion, and metastasis. Mechanistically, STIM2 loss activates cMyc and the PERK/ATF4 branch of ER stress in an Orai-independent manner. Therefore, STIM2 and PERK/ATF4 could be exploited for prognosis or in targeted therapies to inhibit CRC tumor growth and metastasis.
Databáze:	MEDLINE
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