PMID- 33916826
OWN - NLM
STAT- MEDLINE
DCOM- 20211020
LR  - 20231127
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 10
IP  - 4
DP  - 2021 Apr 3
TI  - Lysine 53 Acetylation of Cytochrome c in Prostate Cancer: Warburg Metabolism and 
      Evasion of Apoptosis.
LID - 10.3390/cells10040802 [doi]
LID - 802
AB  - 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 A, 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.
FAU - Bazylianska, Viktoriia
AU  - Bazylianska V
AD  - Center for Molecular Medicine and Genetics, School of Medicine, Wayne State 
      University, Detroit, MI 48201, USA.
AD  - Department of Biochemistry, Microbiology, and Immunology, School of Medicine, 
      Wayne State University, Detroit, MI 48201, USA.
FAU - Kalpage, Hasini A
AU  - Kalpage HA
AD  - Center for Molecular Medicine and Genetics, School of Medicine, Wayne State 
      University, Detroit, MI 48201, USA.
FAU - Wan, Junmei
AU  - Wan J
AD  - Center for Molecular Medicine and Genetics, School of Medicine, Wayne State 
      University, Detroit, MI 48201, USA.
FAU - Vaishnav, Asmita
AU  - Vaishnav A
AD  - Department of Biochemistry, Microbiology, and Immunology, School of Medicine, 
      Wayne State University, Detroit, MI 48201, USA.
FAU - Mahapatra, Gargi
AU  - Mahapatra G
AD  - Center for Molecular Medicine and Genetics, School of Medicine, Wayne State 
      University, Detroit, MI 48201, USA.
AD  - Department of Biochemistry, Microbiology, and Immunology, School of Medicine, 
      Wayne State University, Detroit, MI 48201, USA.
FAU - Turner, Alice A
AU  - Turner AA
AD  - Center for Molecular Medicine and Genetics, School of Medicine, Wayne State 
      University, Detroit, MI 48201, USA.
AD  - Department of Biochemistry, Microbiology, and Immunology, School of Medicine, 
      Wayne State University, Detroit, MI 48201, USA.
FAU - Chowdhury, Dipanwita Dutta
AU  - Chowdhury DD
AD  - Department of Biochemistry, Microbiology, and Immunology, School of Medicine, 
      Wayne State University, Detroit, MI 48201, USA.
FAU - Kim, Katherine
AU  - Kim K
AD  - Center for Molecular Medicine and Genetics, School of Medicine, Wayne State 
      University, Detroit, MI 48201, USA.
FAU - Morse, Paul T
AU  - Morse PT
AUID- ORCID: 0000-0003-1530-1466
AD  - Center for Molecular Medicine and Genetics, School of Medicine, Wayne State 
      University, Detroit, MI 48201, USA.
FAU - Lee, Icksoo
AU  - Lee I
AD  - Center for Molecular Medicine and Genetics, School of Medicine, Wayne State 
      University, Detroit, MI 48201, USA.
AD  - College of Medicine, Dankook University, Cheonan-si, Chungcheongnam-do 31116, 
      Korea.
FAU - Brunzelle, Joseph S
AU  - Brunzelle JS
AD  - Life Sciences Collaborative Access Team, Center for Synchrotron Research, 
      Northwestern University, Argonne, IL 60439, USA.
FAU - Polin, Lisa
AU  - Polin L
AD  - Department of Oncology, Karmanos Cancer Institute, Wayne State University, 
      Detroit, MI 48201, USA.
FAU - Subedi, Prabal
AU  - Subedi P
AD  - Medical Proteomics/Bioanalytics-Center, Ruhr-University Bochum, 44789 Bochum, 
      Germany.
FAU - Heath, Elisabeth I
AU  - Heath EI
AD  - Department of Oncology, Karmanos Cancer Institute, Wayne State University, 
      Detroit, MI 48201, USA.
FAU - Podgorski, Izabela
AU  - Podgorski I
AD  - Department of Pharmacology, Wayne State University, Detroit, MI 48201, USA.
FAU - Marcus, Katrin
AU  - Marcus K
AUID- ORCID: 0000-0002-3313-8845
AD  - Medical Proteomics/Bioanalytics-Center, Ruhr-University Bochum, 44789 Bochum, 
      Germany.
FAU - Edwards, Brian F P
AU  - Edwards BFP
AD  - Department of Biochemistry, Microbiology, and Immunology, School of Medicine, 
      Wayne State University, Detroit, MI 48201, USA.
FAU - Huttemann, Maik
AU  - Huttemann M
AUID- ORCID: 0000-0001-6310-7081
AD  - Center for Molecular Medicine and Genetics, School of Medicine, Wayne State 
      University, Detroit, MI 48201, USA.
AD  - Department of Biochemistry, Microbiology, and Immunology, School of Medicine, 
      Wayne State University, Detroit, MI 48201, USA.
LA  - eng
GR  - P50 CA186786/CA/NCI NIH HHS/United States
GR  - R01 GM116807/GM/NIGMS NIH HHS/United States
GR  - R01 GM116807/NH/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20210403
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Cardiolipins)
RN  - 0 (Reactive Oxygen Species)
RN  - 9007-43-6 (Cytochromes c)
RN  - EC 1.11.1.7 (Peroxidase)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
RN  - EC 3.4.22.- (Caspase 3)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Acetylation
MH  - Animals
MH  - *Apoptosis
MH  - Cardiolipins
MH  - Caspase 3/metabolism
MH  - Cell Line, Tumor
MH  - Crystallography, X-Ray
MH  - Cytochromes c/chemistry/*metabolism
MH  - Electron Transport Complex IV/metabolism
MH  - Humans
MH  - Lysine/*metabolism
MH  - Male
MH  - Mice
MH  - Molecular Dynamics Simulation
MH  - Mutation/genetics
MH  - Oxidation-Reduction
MH  - Oxygen Consumption
MH  - Peroxidase/metabolism
MH  - Prostatic Neoplasms/*metabolism/*pathology
MH  - Prostatic Neoplasms, Castration-Resistant/metabolism/pathology
MH  - Reactive Oxygen Species/metabolism
MH  - *Warburg Effect, Oncologic
MH  - Xenograft Model Antitumor Assays
PMC - PMC8066186
OTO - NOTNLM
OT  - Warburg effect
OT  - acetylation
OT  - apoptosis
OT  - cell signaling
OT  - cytochrome c
OT  - cytochrome c oxidase
OT  - prostate cancer
OT  - reactive oxygen species
COIS- The authors declare that they have no conflict of interest with the contents of 
      this article.
EDAT- 2021/05/01 06:00
MHDA- 2021/10/21 06:00
PMCR- 2021/04/03
CRDT- 2021/04/30 01:04
PHST- 2021/03/05 00:00 [received]
PHST- 2021/03/28 00:00 [revised]
PHST- 2021/04/01 00:00 [accepted]
PHST- 2021/04/30 01:04 [entrez]
PHST- 2021/05/01 06:00 [pubmed]
PHST- 2021/10/21 06:00 [medline]
PHST- 2021/04/03 00:00 [pmc-release]
AID - cells10040802 [pii]
AID - cells-10-00802 [pii]
AID - 10.3390/cells10040802 [doi]
PST - epublish
SO  - Cells. 2021 Apr 3;10(4):802. doi: 10.3390/cells10040802.