Synchronous effects of targeted mitochondrial complex I inhibitors on tumor and immune cells abrogate melanoma progression
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
Mahmoud AbuEid
Department of Microbiology & Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Center for Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Donna M. McAllister
Department of Microbiology & Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Laura McOlash
Department of Microbiology & Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Megan Cleland Harwig
Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Gang Cheng
Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Donovan Drouillard
Department of Microbiology & Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Center for Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Kathleen A. Boyle
Department of Microbiology & Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Micael Hardy
Aix Marseille University, CNRS, ICR, UMR 7273, Marseille 13013, France
Jacek Zielonka
Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Bryon D. Johnson
Center for Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
R. Blake Hill
Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Balaraman Kalyanaraman
Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Michael B. Dwinell
Department of Microbiology & Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Center for Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Corresponding author
Summary: 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.
