title: Metabolic signatures of renal cell carcinoma.
abstract: Clear cell renal cell carcinoma (ccRCC) is characterized by the constitutive up-regulation of the hypoxia inducible factor-1. One of its target enzymes, pyruvate dehydrogenase (PDH) kinase 1 (PDHK1) showed increased protein expression in tumor as compared to patient-matched normal tissues. PDHK1 phosphorylated and inhibited PDH whose enzymatic activity was severely diminished, depriving the TCA cycle of acetylCoA. We and others have shown a decrease in the protein expressions of all respiratory complexes alluding to a compromise in oxidative phosphorylation (OXPHOS). On the contrary, we found that key parameters of OXPHOS, namely ATP biosynthesis and membrane potential were consistently measurable in mitochondria isolated from ccRCC tumor tissues. Interestingly, an endogenous mitochondrial membrane potential (MMP) was evident when ADP was added to mitochondria isolated from ccRCC but not in normal tissues. In addition, the MMP elicited in the presence of ADP by respiratory substrates namely malate/glutamate, succinate, α-ketoglutarate and isocitrate was invariably higher in ccRCC. Two additional hallmarks of ccRCC include a loss of uncoupling protein (UCP)-2 and an increase in UCP-3. Based on our data, we proposed that inhibition of UCP3 by ADP could contribute to the endogenous MMP observed in ccRCC and other cancer cells.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, National University Health Systems, Kent Ridge, Singapore 119260, Singapore.
authors.forename: Hwee Ying
authors.initials: HY
authors.lastname: Lim
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, National University Health Systems, Kent Ridge, Singapore 119260, Singapore.
authors.forename: Yin Mun
authors.initials: YM
authors.lastname: Yip
authors.affiliation: Department of Urology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health Systems, Kent Ridge, Singapore 119260, Singapore.
authors.forename: Edmund
authors.initials: E
authors.lastname: Chiong
authors.affiliation: Department of Urology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health Systems, Kent Ridge, Singapore 119260, Singapore.
authors.forename: Ho Yee
authors.initials: HY
authors.lastname: Tiong
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, National University Health Systems, Kent Ridge, Singapore 119260, Singapore.
authors.forename: Barry
authors.initials: B
authors.lastname: Halliwell
authors.affiliation: Department of Urology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health Systems, Kent Ridge, Singapore 119260, Singapore.
authors.forename: Kesavan
authors.initials: K
authors.lastname: Esuvaranathan
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, National University Health Systems, Kent Ridge, Singapore 119260, Singapore. Electronic address: bchsitkp@nus.edu.sg.
authors.forename: Kim Ping
authors.initials: KP
authors.lastname: Wong
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010085:Oxidative Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D020782:Matrix Metalloproteinases
keywords: Clear cell renal cell carcinoma (ccRCC); Mitochondrial membrane potential (MMP); Oxidative phosphorylation (OXPHOS); Uncoupling protein 2 (UCP2); Uncoupling protein 3 (UCP3); Warburg effect