Synchronous effects of targeted mitochondrial complex I inhibitors on tumor and immune cells abrogate melanoma progression. iScience 2021 Jun 25;24(6):102653
Date
07/01/2021Pubmed ID
34189432Pubmed Central ID
PMC8220235DOI
10.1016/j.isci.2021.102653Scopus ID
2-s2.0-85107963806 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
Metabolic heterogeneity within the tumor microenvironment promotes cancer cell growth and immune suppression. We determined the impact of mitochondria-targeted complex I inhibitors (Mito-CI) in melanoma. Mito-CI decreased mitochondria complex I oxygen consumption, Akt-FOXO signaling, blocked cell cycle progression, melanoma cell proliferation and tumor progression in an immune competent model system. Immune depletion revealed roles for T cells in the antitumor effects of Mito-CI. While Mito-CI preferentially accumulated within and halted tumor cell proliferation, it also elevated infiltration of activated effector T cells and decreased myeloid-derived suppressor cells (MDSC) as well as tumor-associated macrophages (TAM) in melanoma tumors in vivo. Anti-proliferative doses of Mito-CI inhibited differentiation, viability, and the suppressive function of bone marrow-derived MDSC and increased proliferation-independent activation of T cells. These data indicate that targeted inhibition of complex I has synchronous effects that cumulatively inhibits melanoma growth and promotes immune remodeling.
Author List
AbuEid M, McAllister DM, McOlash L, Harwig MC, Cheng G, Drouillard D, Boyle KA, Hardy M, Zielonka J, Johnson BD, Hill RB, Kalyanaraman B, Dwinell MBAuthors
Gang Cheng PhD Assistant Professor in the Biophysics department at Medical College of WisconsinMichael B. Dwinell PhD Director, Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Micael Joel Hardy PhD Visiting Assistant Professor in the Biophysics department at Medical College of Wisconsin
Ronald Blake Hill PhD Professor in the Biochemistry department at Medical College of Wisconsin
Bryon D. Johnson PhD Professor in the Medicine department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin
Jacek M. Zielonka PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin
