The non-canonical mechanism of ER stress-mediated progression of prostate cancer.
| Title: | The non-canonical mechanism of ER stress-mediated progression of prostate cancer. |
|---|---|
| Authors: | Pachikov AN; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; The Fred and Pamela Buffett Cancer Center, Omaha, NE, 68198, USA.; Gough RR; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; The Fred and Pamela Buffett Cancer Center, Omaha, NE, 68198, USA.; Omaha Western Iowa Health Care System, VA Service, Department of Research Service, Omaha, NE, 68105, USA.; Christy CE; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Morris ME; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Casey CA; Omaha Western Iowa Health Care System, VA Service, Department of Research Service, Omaha, NE, 68105, USA.; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68105, USA.; LaGrange CA; Division of Urologic Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Bhat G; School of Basic and Applied Sciences, Dayananda Sagar University, Bangalore, Karnataka, 560078, India.; Kubyshkin AV; Department of Pathological Physiology, Medical Academy named after S. I. Georgievsky, V. I. Vernadsky Crimean Federal University, Simferopol, Russia, 295051.; Fomochkina II; Department of Pathological Physiology, Medical Academy named after S. I. Georgievsky, V. I. Vernadsky Crimean Federal University, Simferopol, Russia, 295051.; Zyablitskaya EY; Laboratory of Molecular Biology, Medical Academy named after S. I. Georgievsky, V. I. Vernadsky Crimean Federal University, Simferopol, Russia, 295051.; Makalish TP; Laboratory of Molecular Biology, Medical Academy named after S. I. Georgievsky, V. I. Vernadsky Crimean Federal University, Simferopol, Russia, 295051.; Golubinskaya EP; Laboratory of Molecular Biology, Medical Academy named after S. I. Georgievsky, V. I. Vernadsky Crimean Federal University, Simferopol, Russia, 295051.; Davydenko KA; Laboratory of Molecular Biology, Medical Academy named after S. I. Georgievsky, V. I. Vernadsky Crimean Federal University, Simferopol, Russia, 295051.; Eremenko SN; Saint Luc's Clinique, V. I. Vernadsky Crimean Federal University, Simferopol, Russia, 295051.; Riethoven JM; Center for Biotechnology, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.; Department of Statistics, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.; The Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.; Maroli AS; The Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.; Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.; Payne TS; Department of Statistics, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.; The Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.; Powers R; The Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.; Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.; Lushnikov AY; Nanoimaging Core Facility, University of Nebraska Medical Center, Omaha, NE, 68105, USA.; Macke AJ; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; Petrosyan A; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA. apetrosyan@unmc.edu.; The Fred and Pamela Buffett Cancer Center, Omaha, NE, 68198, USA. apetrosyan@unmc.edu.; Omaha Western Iowa Health Care System, VA Service, Department of Research Service, Omaha, NE, 68105, USA. apetrosyan@unmc.edu. |
| Source: | Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2021 Sep 14; Vol. 40 (1), pp. 289. Date of Electronic Publication: 2021 Sep 14. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: BioMed Central Country of Publication: England NLM ID: 8308647 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-9966 (Electronic) Linking ISSN: 03929078 NLM ISO Abbreviation: J Exp Clin Cancer Res Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2009- : London : BioMed Central; Original Publication: [Roma] : APSIT |
| MeSH Terms: | Endoplasmic Reticulum Stress*; Endoplasmic Reticulum/*metabolism ; Prostatic Neoplasms/*metabolism; Golgi Apparatus/metabolism ; Metalloendopeptidases/metabolism ; Mitochondrial Proton-Translocating ATPases/genetics ; Mitochondrial Proton-Translocating ATPases/metabolism ; Proprotein Convertases/metabolism ; Prostatic Neoplasms/etiology ; Prostatic Neoplasms/pathology ; Serine Endopeptidases/metabolism ; Animals ; Cell Line, Tumor ; Disease Models, Animal ; Disease Progression ; Heterografts ; Humans ; Male ; Mice ; Protein Binding ; Protein Transport |
| Abstract: | Background: The development of persistent endoplasmic reticulum (ER) stress is one of the cornerstones of prostate carcinogenesis; however, the mechanism is missing. Also, alcohol is a physiological ER stress inducer, and the link between alcoholism and progression of prostate cancer (PCa) is well documented but not well characterized. According to the canonical model, the mediator of ER stress, ATF6, is cleaved sequentially in the Golgi by S1P and S2P proteases; thereafter, the genes responsible for unfolded protein response (UPR) undergo transactivation.; Methods: Cell lines used were non-malignant prostate epithelial RWPE-1 cells, androgen-responsive LNCaP, and 22RV1 cells, as well as androgen-refractory PC-3 cells. We also utilized PCa tissue sections from patients with different Gleason scores and alcohol consumption backgrounds. Several sophisticated approaches were employed, including Structured illumination superresolution microscopy, Proximity ligation assay, Atomic force microscopy, and Nuclear magnetic resonance spectroscopy.; Results: Herein, we identified the trans-Golgi matrix dimeric protein GCC185 as a Golgi retention partner for both S1P and S2P, and in cells lacking GCC185, these enzymes lose intra-Golgi situation. Progression of prostate cancer (PCa) is associated with overproduction of S1P and S2P but monomerization of GCC185 and its downregulation. Utilizing different ER stress models, including ethanol administration, we found that PCa cells employ an elegant mechanism that auto-activates ER stress by fragmentation of Golgi, translocation of S1P and S2P from Golgi to ER, followed by intra-ER cleavage of ATF6, accelerated UPR, and cell proliferation. The segregation of S1P and S2P from Golgi and activation of ATF6 are positively correlated with androgen receptor signaling, different disease stages, and alcohol consumption. Finally, depletion of ATF6 significantly retarded the growth of xenograft prostate tumors and blocks production of pro-metastatic metabolites.; Conclusions: We found that progression of PCa associates with translocation of S1P and S2P proteases to the ER and subsequent ATF6 cleavage. This obviates the need for ATF6 transport to the Golgi and enhances UPR and cell proliferation. Thus, we provide the novel mechanistic model of ATF6 activation and ER stress implication in the progression of PCa, suggesting ATF6 is a novel promising target for prostate cancer therapy.; (© 2021. The Author(s).) |
| References: | J Clin Invest. 2017 Jan 3;127(1):117-131. (PMID: 27869652); Cancer. 1991 Jun 15;67(12):3057-64. (PMID: 1710537); Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6561-6. (PMID: 21464300); Am J Clin Pathol. 2011 Jul;136(1):98-107. (PMID: 21685037); Int J Cancer. 2017 Jan 1;140(1):75-85. (PMID: 27643404); Cancer Res. 2019 Sep 15;79(18):4580-4581. (PMID: 31519776); Int J Cancer. 2010 Dec 1;127(11):2685-98. (PMID: 20178102); Curr Opin Oncol. 2017 Jan;29(1):41-47. (PMID: 27845970); Biochemistry (Mosc). 2019 Dec;84(12):1490-1501. (PMID: 31870253); Dev Cell. 2002 Jul;3(1):99-111. (PMID: 12110171); J Biol Chem. 2012 Nov 2;287(45):37621-7. (PMID: 22988244); J Carcinog. 2011;10:20. (PMID: 21886458); Am J Pathol. 2020 May;190(5):934-946. (PMID: 32112719); Cells. 2019 Dec 13;8(12):. (PMID: 31847122); Mod Pathol. 2011 Sep;24(9):1272-80. (PMID: 21572396); Biomolecules. 2018 Nov 16;8(4):. (PMID: 30453527); Traffic. 2007 Jun;8(6):758-73. (PMID: 17488291); BMC Cancer. 2016 Nov 15;16(1):845. (PMID: 27842506); Int J Cancer. 2013 Dec 15;133(12):2914-24. (PMID: 23737455); Mol Endocrinol. 2009 Dec;23(12):1963-72. (PMID: 19855091); Sci Rep. 2015 Apr 16;5:9698. (PMID: 25880275); Science. 2012 May 25;336(6084):1040-4. (PMID: 22628656); Biochem Mol Biol J. 2015;1(1):. (PMID: 27064441); Trends Cell Biol. 2003 Jun;13(6):279-81. (PMID: 12791290); Biochim Biophys Acta. 2015 Oct;1848(10 Pt B):2502-11. (PMID: 25150047); Trends Biochem Sci. 2016 Mar;41(3):211-218. (PMID: 26778478); Cancer Res. 2007 Nov 15;67(22):10631-4. (PMID: 18006802); Mol Cancer Res. 2019 Jan;17(1):225-237. (PMID: 30224543); J Biol Chem. 2004 Nov 5;279(45):46384-92. (PMID: 15319438); Traffic. 2016 Jul;17(7):733-53. (PMID: 27062250); Biochem Res Int. 2012;2012:216450. (PMID: 22110961); Cancer Res. 2018 Feb 15;78(4):1044-1057. (PMID: 29259014); Acta Oncol. 2012 Sep;51(7):822-30. (PMID: 22686473); J Cell Sci. 1993 Jul;105 ( Pt 3):819-30. (PMID: 7691849); Mol Nutr Food Res. 2009 Feb;53(2):240-55. (PMID: 19156715); Oncotarget. 2016 Aug 16;7(33):54051-54066. (PMID: 27303918); J Biol Chem. 2004 Oct 8;279(41):43046-51. (PMID: 15299016); BMC Cancer. 2011 Jun 07;11:229. (PMID: 21649922); Cell. 1999 Dec 23;99(7):703-12. (PMID: 10619424); Mol Cancer Res. 2014 Dec;12(12):1704-16. (PMID: 25086069); Sci Rep. 2017 Apr 24;7(1):1109. (PMID: 28439080); Mol Endocrinol. 1997 Feb;11(2):148-61. (PMID: 9013762); Krim Z Eksp Klin Med. 2018;8(4):11-20. (PMID: 31131224); BMC Cancer. 2017 Feb 20;17(1):145. (PMID: 28219369); FEBS Lett. 2002 Apr 10;516(1-3):217-24. (PMID: 11959136); J Cancer Prev. 2014 Jun;19(2):75-88. (PMID: 25337575); Biochem J. 2011 Apr 1;435(1):285-96. (PMID: 21241252); Cell Death Dis. 2013 Apr 25;4:e607. (PMID: 23618905) |
| Grant Information: | R01AA020735 United States AA NIAAA NIH HHS; P20 GM113126 United States GM NIGMS NIH HHS; R01 AA027242 United States AA NIAAA NIH HHS; I01BX004171 Office of Academic Affiliations, Department of Veterans Affairs; R01 AA020735 United States AA NIAAA NIH HHS; I01 BX004171 United States BX BLRD VA |
| Contributed Indexing: | Keywords: Alcohol abuse; ER stress; Golgi fragmentation; Prostate cancer |
| Substance Nomenclature: | 0 (MT-ATP6 protein, human); EC 3.4.21.- (Proprotein Convertases); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.112 (membrane-bound transcription factor peptidase, site 1); EC 3.4.24.- (Metalloendopeptidases); EC 3.4.24.85 (MBTPS2 protein, human); EC 3.6.3.- (Mitochondrial Proton-Translocating ATPases) |
| Entry Date(s): | Date Created: 20210915 Date Completed: 20220117 Latest Revision: 20260409 |
| Update Code: | 20260409 |
| PubMed Central ID: | PMC8439065 |
| DOI: | 10.1186/s13046-021-02066-7 |
| PMID: | 34521429 |
| Database: | MEDLINE |
Journal Article