PMID- 35723497
OWN - NLM
STAT- MEDLINE
DCOM- 20220811
LR  - 20230902
IS  - 1098-2744 (Electronic)
IS  - 0899-1987 (Print)
IS  - 0899-1987 (Linking)
VI  - 61
IP  - 9
DP  - 2022 Sep
TI  - Targeting mitochondrial metabolism for metastatic cancer therapy.
PG  - 827-838
LID - 10.1002/mc.23436 [doi]
AB  - Primary tumors evolve metabolic mechanisms favoring glycolysis for adenosine 
      triphosphate (ATP) generation and antioxidant defenses. In contrast, metastatic 
      cells frequently depend on mitochondrial respiration and oxidative 
      phosphorylation (OxPhos). This reliance of metastatic cells on OxPhos can be 
      exploited using drugs that target mitochondrial metabolism. Therefore, 
      therapeutic agents that act via diverse mechanisms, including the activation of 
      signaling pathways that promote the production of reactive oxygen species (ROS) 
      and/or a reduction in antioxidant defenses may elevate oxidative stress and 
      inhibit tumor cell survival. In this review, we will provide (1) a mechanistic 
      analysis of function-selective extracellular signal-regulated kinase-1/2 (ERK1/2) 
      inhibitors that inhibit cancer cells through enhanced ROS, (2) a review of the 
      role of mitochondrial ATP synthase in redox regulation and drug resistance, (3) a 
      rationale for inhibiting ERK signaling and mitochondrial OxPhos toward the 
      therapeutic goal of reducing tumor metastasis and treatment resistance. Recent 
      reports from our laboratories using metastatic melanoma and breast cancer models 
      have shown the preclinical efficacy of novel and rationally designed therapeutic 
      agents that target ERK1/2 signaling and mitochondrial ATP synthase, which 
      modulate ROS events that may prevent or treat metastatic cancer. These findings 
      and those of others suggest that targeting a tumor's metabolic requirements and 
      vulnerabilities may inhibit metastatic pathways and tumor growth. Approaches that 
      exploit the ability of therapeutic agents to alter oxidative balance in tumor 
      cells may be selective for cancer cells and may ultimately have an impact on 
      clinical efficacy and safety. Elucidating the translational potential of 
      metabolic targeting could lead to the discovery of new approaches for treatment 
      of metastatic cancer.
CI  - (c) 2022 Wiley Periodicals LLC.
FAU - Passaniti, Antonino
AU  - Passaniti A
AD  - The Veteran's Health Administration Research & Development Service (VAMHCS), VA 
      Maryland Health Care System (VAMHCS), Baltimore VA Medical Center, Baltimore, 
      Maryland, USA.
AD  - Department of Pathology and Department of Biochemistry & Molecular Biology, The 
      Program in Molecular Medicine and the Marlene & Stewart Greenebaum Comprehensive 
      Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, 
      USA.
FAU - Kim, Myoung Sook
AU  - Kim MS
AD  - Department of Pathology and Department of Biochemistry & Molecular Biology, The 
      Program in Molecular Medicine and the Marlene & Stewart Greenebaum Comprehensive 
      Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, 
      USA.
FAU - Polster, Brian M
AU  - Polster BM
AD  - Department of Anesthesiology, University of Maryland School of Medicine, 
      Baltimore, Maryland, USA.
FAU - Shapiro, Paul
AU  - Shapiro P
AD  - Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 
      Baltimore, Maryland, USA.
LA  - eng
GR  - I01 BX004904/BX/BLRD VA/United States
GR  - R01 CA120215/CA/NCI 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.
PT  - Review
DEP - 20220620
PL  - United States
TA  - Mol Carcinog
JT  - Molecular carcinogenesis
JID - 8811105
RN  - 0 (Antioxidants)
RN  - 0 (Reactive Oxygen Species)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 3.6.3.- (Mitochondrial Proton-Translocating ATPases)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Antioxidants
MH  - Humans
MH  - Mitochondria/metabolism
MH  - *Mitochondrial Proton-Translocating ATPases/metabolism
MH  - *Neoplasms/metabolism
MH  - Oxidative Phosphorylation
MH  - Reactive Oxygen Species/metabolism
PMC - PMC9378505
MID - NIHMS1812984
OTO - NOTNLM
OT  - cancer metastasis
OT  - drug mechanisms
OT  - kinase signaling
OT  - mitochondria
OT  - reactive oxygen species
OT  - targeting OxPhos
COIS- CONFLICTS OF INTERESTS The authors declare that there are no conflicts of 
      interest. The contents do not represent the views of the U.S. Department of 
      Veterans Affairs or the United States Government.
EDAT- 2022/06/21 06:00
MHDA- 2022/08/12 06:00
PMCR- 2023/09/01
CRDT- 2022/06/20 09:06
PHST- 2022/05/18 00:00 [revised]
PHST- 2021/12/28 00:00 [received]
PHST- 2022/05/27 00:00 [accepted]
PHST- 2022/06/21 06:00 [pubmed]
PHST- 2022/08/12 06:00 [medline]
PHST- 2022/06/20 09:06 [entrez]
PHST- 2023/09/01 00:00 [pmc-release]
AID - 10.1002/mc.23436 [doi]
PST - ppublish
SO  - Mol Carcinog. 2022 Sep;61(9):827-838. doi: 10.1002/mc.23436. Epub 2022 Jun 20.