Targeting the ATF6-Mediated ER Stress Response and Autophagy Blocks Integrin-Driven Prostate Cancer Progression

Author:

Macke Amanda J.12ORCID,Pachikov Artem N.12ORCID,Divita Taylor E.12ORCID,Morris Mary E.1ORCID,LaGrange Chad A.3ORCID,Holzapfel Melissa S.4ORCID,Kubyshkin Anatoly V.5ORCID,Zyablitskaya Evgeniya Y.6ORCID,Makalish Tatiana P.6ORCID,Eremenko Sergey N.7ORCID,Qiu Haowen8ORCID,Riethoven Jean-Jack M.89ORCID,Hemstreet George P.310ORCID,Petrosyan Armen12ORCID

Affiliation:

1. 1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.

2. 2The Fred and Pamela Buffett Cancer Center, Omaha, Nebraska.

3. 3Division of Urologic Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska.

4. 4Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.

5. 5Department of Pathological Physiology, Medical Academy named after S.I. Georgievsky, V.I. Vernadsky Crimean Federal University, Simferopol, Russia.

6. 6Laboratory of Molecular Biology, Medical Academy named after S.I. Georgievsky, V.I. Vernadsky Crimean Federal University, Simferopol, Russia.

7. 7Saint Luc's Clinique, V.I. Vernadsky Crimean Federal University, Simferopol, Russia.

8. 8Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, Nebraska.

9. 9Department of Statistics, University of Nebraska-Lincoln, Lincoln, Nebraska.

10. 10Omaha Western Iowa Health Care System Urology, VA Service, Department of Research Service, Omaha, Nebraska.

Abstract

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.

Funder

Foundation for the National Institutes of Health

National Institute of General Medical Sciences

Government Council on Grants, Russian Federation

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology,Molecular Biology

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