Targeting the ATF6-Mediated ER Stress Response and Autophagy Blocks Integrin-Driven Prostate Cancer Progression.
| Title: | Targeting the ATF6-Mediated ER Stress Response and Autophagy Blocks Integrin-Driven Prostate Cancer Progression. |
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| Authors: | Macke AJ; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.; The Fred and Pamela Buffett Cancer Center, Omaha, Nebraska.; Pachikov AN; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.; The Fred and Pamela Buffett Cancer Center, Omaha, Nebraska.; Divita TE; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.; The Fred and Pamela Buffett Cancer Center, Omaha, Nebraska.; Morris ME; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.; LaGrange CA; Division of Urologic Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska.; Holzapfel MS; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.; Kubyshkin AV; Department of Pathological Physiology, Medical Academy named after S.I. Georgievsky, V.I. Vernadsky Crimean Federal University, Simferopol, Russia.; Zyablitskaya EY; Laboratory of Molecular Biology, Medical Academy named after S.I. Georgievsky, V.I. Vernadsky Crimean Federal University, Simferopol, Russia.; Makalish TP; Laboratory of Molecular Biology, Medical Academy named after S.I. Georgievsky, V.I. Vernadsky Crimean Federal University, Simferopol, Russia.; Eremenko SN; Saint Luc's Clinique, V.I. Vernadsky Crimean Federal University, Simferopol, Russia.; Qiu H; Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, Nebraska.; Riethoven JM; Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, Nebraska.; Department of Statistics, University of Nebraska-Lincoln, Lincoln, Nebraska.; Hemstreet GP; Division of Urologic Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska.; Omaha Western Iowa Health Care System Urology, VA Service, Department of Research Service, Omaha, Nebraska.; Petrosyan A; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.; The Fred and Pamela Buffett Cancer Center, Omaha, Nebraska. |
| Source: | Molecular cancer research : MCR [Mol Cancer Res] 2023 Sep 01; Vol. 21 (9), pp. 958-974. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101150042 Publication Model: Print Cited Medium: Internet ISSN: 1557-3125 (Electronic) Linking ISSN: 15417786 NLM ISO Abbreviation: Mol Cancer Res Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Philadelphia, PA : American Association for Cancer Research, c2002- |
| MeSH Terms: | Prostatic Neoplasms, Castration-Resistant*/drug therapy ; Prostatic Neoplasms, Castration-Resistant*/genetics ; N-Acetylglucosaminyltransferases*; Activating Transcription Factor 6/genetics ; Activating Transcription Factor 6/metabolism ; Humans ; Male ; Integrins ; Integrin alphaV ; Endoplasmic Reticulum Stress ; Autophagy |
| Abstract: | Prostate cancer progression to the lethal metastatic castration-resistant phenotype (mCRPC) is driven by αv integrins and is associated with Golgi disorganization and activation of the ATF6 branch of unfolded protein response (UPR). Overexpression of integrins requires N-acetylglucosaminyltransferase-V (MGAT5)-mediated glycosylation and subsequent cluster formation with Galectin-3 (Gal-3). However, the mechanism underlying this altered glycosylation is missing. For the first time, using HALO analysis of IHC, we found a strong association of integrin αv and Gal-3 at the plasma membrane (PM) in primary prostate cancer and mCRPC samples. We discovered that MGAT5 activation is caused by Golgi fragmentation and mislocalization of its competitor, N-acetylglucosaminyltransferase-III, MGAT3, from Golgi to the endoplasmic reticulum (ER). This was validated in an ethanol-induced model of ER stress, where alcohol treatment in androgen-refractory PC-3 and DU145 cells or alcohol consumption in patient with prostate cancer samples aggravates Golgi scattering, activates MGAT5, and enhances integrin expression at PM. This explains known link between alcohol consumption and prostate cancer mortality. ATF6 depletion significantly blocks UPR and reduces the number of Golgi fragments in both PC-3 and DU145 cells. Inhibition of autophagy by hydroxychloroquine (HCQ) restores compact Golgi, rescues MGAT3 intra-Golgi localization, blocks glycan modification via MGAT5, and abrogates delivery of Gal-3 to the cell surface. Importantly, the loss of Gal-3 leads to reduced integrins at PM and their accelerated internalization. ATF6 depletion and HCQ treatment synergistically decrease integrin αv and Gal-3 expression and temper orthotopic tumor growth and metastasis.; Implications: Combined ablation of ATF6 and autophagy can serve as new mCRPC therapeutic.; (©2023 American Association for Cancer Research.) |
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| Grant Information: | F31 AA031186 United States AA NIAAA NIH HHS; I01 BX004171 United States BX BLRD VA; P20 GM113126 United States GM NIGMS NIH HHS; R01 AA027242 United States AA NIAAA NIH HHS |
| Substance Nomenclature: | EC 2.4.1.- (N-Acetylglucosaminyltransferases); 0 (Integrins); 0 (Integrin alphaV); 0 (ATF6 protein, human); 0 (Activating Transcription Factor 6) |
| Entry Date(s): | Date Created: 20230614 Date Completed: 20230904 Latest Revision: 20240411 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10527559 |
| DOI: | 10.1158/1541-7786.MCR-23-0108 |
| PMID: | 37314749 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't