Synchronous Effects of Targeted Mitochondrial Complex I Inhibitors on Tumor and Immune Cells Abrogate Melanoma Progression

Overview

Journal iScience

Publisher Cell Press

Date 2021 Jun 30

PMID 34189432

Citations 15

Authors

Mahmoud AbuEid

Donna M McAllister

Laura McOlash

Megan Cleland Harwig

Gang Cheng

Donovan Drouillard

Kathleen A Boyle

Micael Hardy

Jacek Zielonka

Bryon D Johnson

R Blake Hill

Balaraman Kalyanaraman

Michael B Dwinell

Affiliations

Soon will be listed here.

Abstract

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 . 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.

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