Lysine 53 Acetylation of Cytochrome c in Prostate Cancer: Warburg Metabolism and Evasion of Apoptosis

Bazylianska, Viktoriia; Kalpage, Hasini A.; Wan, Junmei; Vaishnav, Asmita; Mahapatra, Gargi; Turner, Alice A.; Chowdhury, Dipanwita Dutta; Kim, Katherine; Morse, Paul T.; Lee, Icksoo; Brunzelle, Joseph S.; Polin, Lisa; Subedi, Prabal; Heath, Elisabeth I.; Podgorski, Izabela; Marcus, Katrin; Edwards, Brian F.P.; Hüttemann, Maik

doi:10.3390/cells10040802

Open AccessArticle

Lysine 53 Acetylation of Cytochrome c in Prostate Cancer: Warburg Metabolism and Evasion of Apoptosis

by

Viktoriia Bazylianska

^1,2,†,

Hasini A. Kalpage

^1,†,

Junmei Wan

^1,†

,

Asmita Vaishnav

²,

Gargi Mahapatra

^1,2,‡,

Alice A. Turner

^1,2,

Dipanwita Dutta Chowdhury

²,

Katherine Kim

¹,

Paul T. Morse

¹

,

Icksoo Lee

^1,3,

Joseph S. Brunzelle

⁴,

Lisa Polin

⁵,

Prabal Subedi

⁶,

Elisabeth I. Heath

⁵,

Izabela Podgorski

⁷,

Katrin Marcus

⁶

,

Brian F.P. Edwards

² and

Maik Hüttemann

^1,2,*

¹

Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA

²

Department of Biochemistry, Microbiology, and Immunology, School of Medicine, Wayne State University, Detroit, MI 48201, USA

³

College of Medicine, Dankook University, Cheonan-si, Chungcheongnam-do 31116, Korea

⁴

Life Sciences Collaborative Access Team, Center for Synchrotron Research, Northwestern University, Argonne, IL 60439, USA

⁵

Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA

⁶

Medical Proteomics/Bioanalytics-Center, Ruhr-University Bochum, 44789 Bochum, Germany

⁷

Department of Pharmacology, Wayne State University, Detroit, MI 48201, USA

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

^‡

Present address: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.

Cells 2021, 10(4), 802; https://doi.org/10.3390/cells10040802

Submission received: 5 March 2021 / Revised: 28 March 2021 / Accepted: 1 April 2021 / Published: 3 April 2021

(This article belongs to the Special Issue Oxidative Phosphorylation and Hormones: Different Ways of Influence)

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Abstract

Prostate cancer is the second leading cause of cancer-related death in men. Two classic cancer hallmarks are a metabolic switch from oxidative phosphorylation (OxPhos) to glycolysis, known as the Warburg effect, and resistance to cell death. Cytochrome c (Cytc) is at the intersection of both pathways, as it is essential for electron transport in mitochondrial respiration and a trigger of intrinsic apoptosis when released from the mitochondria. However, its functional role in cancer has never been studied. Our data show that Cytc is acetylated on lysine 53 in both androgen hormone-resistant and -sensitive human prostate cancer xenografts. To characterize the functional effects of K53 modification in vitro, K53 was mutated to acetylmimetic glutamine (K53Q), and to arginine (K53R) and isoleucine (K53I) as controls. Cytochrome c oxidase (COX) activity analyzed with purified Cytc variants showed reduced oxygen consumption with acetylmimetic Cytc compared to the non-acetylated Cytc (WT), supporting the Warburg effect. In contrast to WT, K53Q Cytc had significantly lower caspase-3 activity, suggesting that modification of Cytc K53 helps cancer cells evade apoptosis. Cardiolipin peroxidase activity, which is another proapoptotic function of the protein, was lower in acetylmimetic Cytc. Acetylmimetic Cytc also had a higher capacity to scavenge reactive oxygen species (ROS), another pro-survival feature. We discuss our experimental results in light of structural features of K53Q Cytc, which we crystallized at a resolution of 1.31 Å, together with molecular dynamics simulations. In conclusion, we propose that K53 acetylation of Cytc affects two hallmarks of cancer by regulating respiration and apoptosis in prostate cancer xenografts.

Keywords: cytochrome c; prostate cancer; acetylation; Warburg effect; cytochrome c oxidase; apoptosis; reactive oxygen species; cell signaling

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MDPI and ACS Style

Bazylianska, V.; Kalpage, H.A.; Wan, J.; Vaishnav, A.; Mahapatra, G.; Turner, A.A.; Chowdhury, D.D.; Kim, K.; Morse, P.T.; Lee, I.; et al. Lysine 53 Acetylation of Cytochrome c in Prostate Cancer: Warburg Metabolism and Evasion of Apoptosis. Cells 2021, 10, 802. https://doi.org/10.3390/cells10040802

AMA Style

Bazylianska V, Kalpage HA, Wan J, Vaishnav A, Mahapatra G, Turner AA, Chowdhury DD, Kim K, Morse PT, Lee I, et al. Lysine 53 Acetylation of Cytochrome c in Prostate Cancer: Warburg Metabolism and Evasion of Apoptosis. Cells. 2021; 10(4):802. https://doi.org/10.3390/cells10040802

Chicago/Turabian Style

Bazylianska, Viktoriia, Hasini A. Kalpage, Junmei Wan, Asmita Vaishnav, Gargi Mahapatra, Alice A. Turner, Dipanwita Dutta Chowdhury, Katherine Kim, Paul T. Morse, Icksoo Lee, and et al. 2021. "Lysine 53 Acetylation of Cytochrome c in Prostate Cancer: Warburg Metabolism and Evasion of Apoptosis" Cells 10, no. 4: 802. https://doi.org/10.3390/cells10040802

APA Style

Bazylianska, V., Kalpage, H. A., Wan, J., Vaishnav, A., Mahapatra, G., Turner, A. A., Chowdhury, D. D., Kim, K., Morse, P. T., Lee, I., Brunzelle, J. S., Polin, L., Subedi, P., Heath, E. I., Podgorski, I., Marcus, K., Edwards, B. F. P., & Hüttemann, M. (2021). Lysine 53 Acetylation of Cytochrome c in Prostate Cancer: Warburg Metabolism and Evasion of Apoptosis. Cells, 10(4), 802. https://doi.org/10.3390/cells10040802

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Lysine 53 Acetylation of Cytochrome c in Prostate Cancer: Warburg Metabolism and Evasion of Apoptosis

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