Mitochondrial p32 protein is a critical regulator of tumor metabolism via maintenance of oxidative phosphorylation.
p32/gC1qR/C1QBP/HABP1 is a mitochondrial/cell surface protein overexpressed in certain cancer cells. Here we show that knocking down p32 expression in human cancer cells strongly shifts their metabolism from oxidative phosphorylation (OXPHOS) to glycolysis. The p32 knockdown cells exhibited reduced synthesis of the mitochondrial-DNA-encoded OXPHOS polypeptides and were less tumorigenic in vivo. Expression of exogenous p32 in the knockdown cells restored the wild-type cellular phenotype and tumorigenicity. Increased glucose consumption and lactate production, known as the Warburg effect, are almost universal hallmarks of solid tumors and are thought to favor tumor growth. However, here we show that a protein regularly overexpressed in some cancers is capable of promoting OXPHOS. Our results indicate that high levels of glycolysis, in the absence of adequate OXPHOS, may not be as beneficial for tumor growth as generally thought and suggest that tumor cells use p32 to regulate the balance between OXPHOS and glycolysis.
Fogal
Valentina
V
Cancer Research Center, Burnham Institute for Medical Research, 10901 N Torrey Pines Rd, La Jolla, California 92037, USA.
Richardson
Adam D
AD
Karmali
Priya P
PP
Scheffler
Immo E
IE
Smith
Jeffrey W
JW
Ruoslahti
Erkki
E
D000818:Animals; D002244:Carbon / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D055785:Gene Knockdown Techniques; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D012402:Rotenone / Q000494:pharmacology
C087299:C1QBP protein, human; D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D012402:Rotenone; D002244:Carbon; D042967:Electron Transport Complex I