Sigma1 Regulates Lipid Droplet-mediated Redox Homeostasis Required for Prostate Cancer Proliferation.

Autor:	Oyer HM; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania., Steck AR; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania., Longen CG; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania., Venkat S; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania., Bayrak K; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania., Munger EB; Department of Chemistry, University of Washington, Seattle, Washington., Fu D; Department of Chemistry, University of Washington, Seattle, Washington., Castagnino PA; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania., Sanders CM; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania., Tancler NA; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania., Mai MT; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania., Myers JP; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania., Schiewer MJ; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania.; Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania., Chen N; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania., Mostaghel EA; Department of Medicine, University of Washington, Seattle, Washington.; Geriatric Research, Education and Clinical Center, U.S. Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington., Kim FJ; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center at Jefferson, Philadelphia, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2023 Oct 30; Vol. 3 (10), pp. 2195-2210.
DOI:	10.1158/2767-9764.CRC-22-0371
Abstrakt:	Lipid droplets (LD) are dynamic organelles that serve as hubs of cellular metabolic processes. Emerging evidence shows that LDs also play a critical role in maintaining redox homeostasis and can mitigate lipid oxidative stress. In multiple cancers, including prostate cancer, LD accumulation is associated with cancer aggressiveness, therapy resistance, and poor clinical outcome. Prostate cancer arises as an androgen receptor (AR)-driven disease. Among its myriad roles, AR mediates the biosynthesis of LDs, induces autophagy, and modulates cellular oxidative stress in a tightly regulated cycle that promotes cell proliferation. The factors regulating the interplay of these metabolic processes downstream of AR remain unclear. Here, we show that Sigma1/SIGMAR1, a unique ligand-operated scaffolding protein, regulates LD metabolism in prostate cancer cells. Sigma1 inhibition triggers lipophagy, an LD selective form of autophagy, to prevent accumulation of LDs which normally act to sequester toxic levels of reactive oxygen species (ROS). This disrupts the interplay between LDs, autophagy, buffering of oxidative stress and redox homeostasis, and results in the suppression of cell proliferation in vitro and tumor growth in vivo. Consistent with these experimental results, SIGMAR1 transcripts are strongly associated with lipid metabolism and ROS pathways in prostate tumors. Altogether, these data reveal a novel, pharmacologically responsive role for Sigma1 in regulating the redox homeostasis required by oncogenic metabolic programs that drive prostate cancer proliferation. Significance: To proliferate, cancer cells must maintain productive metabolic and oxidative stress (eustress) while mitigating destructive, uncontrolled oxidative stress (distress). LDs are metabolic hubs that enable adaptive responses to promote eustress. Targeting the unique Sigma1 protein can trigger distress by disrupting the LD-mediated homeostasis required for proliferation. (© 2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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