MIRO2 Regulates Prostate Cancer Cell Growth via GCN1-Dependent Stress Signaling
Abstract
There is a continued need to identify novel therapeutic targets to prevent the mortality associated with prostate cancer. In this context, mitochondrial Rho GTPase 2 (MIRO2) mRNA was upregulated in metastatic prostate cancer compared with localized tumors, and higher MIRO2 levels were correlated with poor patient survival. Using human cell lines that represent androgen-independent or -sensitive prostate cancer, we showed that MIRO2 depletion impaired cell growth, colony formation, and tumor growth in mice. Network analysis of MIRO2′s binding partners identified metabolism and cellular responses to extracellular stimuli as top overrepresented pathways. The top hit on our screen, General Control Nonderepressible 1 (GCN1), was overexpressed in prostate cancer, and interacted with MIRO2 in prostate cancer cell lines and in primary prostate cancer cells. Functional analysis of MIRO2 mutations present in patients with prostate cancer led to the identification of MIRO2 159L, which increased GCN1 binding. Importantly, MIRO2 was necessary for efficient GCN1-mediated GCN2 kinase signaling and induction of the transcription factor activating transcription factor 4 (ATF4) levels. Further, MIRO2′s effect on regulating prostate cancer cell growth was mediated by ATF4. Finally, levels of activated GCN2 and ATF4 were correlated with MIRO2 expression in prostate cancer xenografts. Both MIRO2 and activated GCN2 levels were higher in hypoxic areas of prostate cancer xenografts. Overall, we propose that targeting the MIRO2-GCN1 axis may be a valuable strategy to halt prostate cancer growth.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 06, 2022
- Source ID
- 10.1158/1541-7786.mcr-21-0374
Entities
People
- Denisa Grofova
- Dillon P. Boulton
- Lina Romero
- M Cecilia Caino
- M. Scott Lucia
- Madison Furnish
- Mitchell Lee Ellinwood
- Scott D. Cramer
- Victoria Genther
Organizations
- American Cancer Society
- Boettcher Foundation
- National Institutes of Health
- University of Colorado