PMID- 31596927
OWN - NLM
STAT- MEDLINE
DCOM- 20200127
LR  - 20240421
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Print)
IS  - 0146-0404 (Linking)
VI  - 60
IP  - 13
DP  - 2019 Oct 1
TI  - Elevated Endogenous SDHA Drives Pathological Metabolism in Highly Metastatic 
      Uveal Melanoma.
PG  - 4187-4195
LID - 10.1167/iovs.19-28082 [doi]
AB  - PURPOSE: Metastatic uveal melanoma (UM) has a very poor prognosis and no 
      effective therapy. Despite remarkable advances in treatment of cutaneous 
      melanoma, UM remains recalcitrant to chemotherapy, small-molecule kinase 
      inhibitors, and immune-based therapy. METHODS: We assessed two sets of oxidative 
      phosphorylation (OxPhos) genes within 9858 tumors across 31 cancer types. An 
      OxPhos inhibitor was used to characterize differential metabolic programming of 
      highly metastatic monosomy 3 (M3) UM. Seahorse analysis and global metabolomics 
      profiling were done to identify metabolic vulnerabilities. Analyses of UM TCGA 
      data set were performed to determine expressions of key OxPhos effectors in M3 
      and non-M3 UM. We used targeted knockdown of succinate dehydrogenase A (SDHA) to 
      determine the role of SDHA in M3 UM in conferring resistance to OxPhos 
      inhibition. RESULTS: We identified UM to have among the highest median OxPhos 
      levels and showed that M3 UM exhibits a distinct metabolic profile. M3 UM shows 
      markedly low succinate levels and has highly increased levels of SDHA, the enzyme 
      that couples the tricarboxylic acid cycle with OxPhos by oxidizing (lowering) 
      succinate. We showed that SDHA-high M3 UM have elevated expression of key OxPhos 
      molecules, exhibit abundant mitochondrial reserve respiratory capacity, and are 
      resistant to OxPhos antagonism, which can be reversed by SDHA knockdown. 
      CONCLUSIONS: Our study has identified a critical metabolic program within poor 
      prognostic M3 UM. In addition to the heightened mitochondrial functional capacity 
      due to elevated SDHA, M3 UM SDHA-high mediate resistance to therapy that is 
      reversible with targeted treatment.
FAU - Chattopadhyay, Chandrani
AU  - Chattopadhyay C
AD  - Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, Texas, United 
      States.
FAU - Oba, Junna
AU  - Oba J
AD  - Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, Texas, United 
      States.
FAU - Roszik, Jason
AU  - Roszik J
AD  - Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, Texas, United 
      States.
AD  - Genomic Medicine, UT MD Anderson Cancer Center, Houston, Texas, United States.
FAU - Marszalek, Joseph R
AU  - Marszalek JR
AD  - Institute of Applied Cancer Science & Center for Co-Clinical Trials, UT MD 
      Anderson Cancer Center, Houston, Texas, United States.
FAU - Chen, Ken
AU  - Chen K
AD  - Bioinformatics & Computational Biology, UT MD Anderson Cancer Center, Houston, 
      Texas, United States.
FAU - Qi, Yuan
AU  - Qi Y
AD  - Bioinformatics & Computational Biology, UT MD Anderson Cancer Center, Houston, 
      Texas, United States.
FAU - Eterovic, Karina
AU  - Eterovic K
AD  - Bioinformatics & Computational Biology, UT MD Anderson Cancer Center, Houston, 
      Texas, United States.
FAU - Robertson, A Gordon
AU  - Robertson AG
AD  - Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, 
      British Columbia, Canada.
FAU - Burks, Jared K
AU  - Burks JK
AD  - Leukemia, UT MD Anderson Cancer Center, Houston, Texas, United States.
FAU - McCannel, Tara A
AU  - McCannel TA
AD  - Stein Eye and Doheny Eye Institutes, University of California Los Angeles, Los 
      Angeles, California, United States.
FAU - Grimm, Elizabeth A
AU  - Grimm EA
AD  - Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, Texas, United 
      States.
FAU - Woodman, Scott E
AU  - Woodman SE
AD  - Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, Texas, United 
      States.
AD  - Systems Biology, UT MD Anderson Cancer Center, Houston, Texas, United States.
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - P50 CA093459/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 0 (SDHD protein, human)
RN  - AB6MNQ6J6L (Succinic Acid)
RN  - EC 1.3.99.1 (Succinate Dehydrogenase)
RN  - Uveal melanoma
SB  - IM
MH  - Humans
MH  - Melanoma/*metabolism
MH  - Oxidative Phosphorylation
MH  - Succinate Dehydrogenase/metabolism/*physiology
MH  - Succinic Acid/metabolism
MH  - Tumor Cells, Cultured
MH  - Uveal Neoplasms/*metabolism
PMC - PMC6785781
EDAT- 2019/10/10 06:00
MHDA- 2020/01/28 06:00
PMCR- 2019/10/01
CRDT- 2019/10/10 06:00
PHST- 2019/10/10 06:00 [entrez]
PHST- 2019/10/10 06:00 [pubmed]
PHST- 2020/01/28 06:00 [medline]
PHST- 2019/10/01 00:00 [pmc-release]
AID - 2753001 [pii]
AID - IOVS-19-28082R1 [pii]
AID - 10.1167/iovs.19-28082 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2019 Oct 1;60(13):4187-4195. doi: 
      10.1167/iovs.19-28082.