title: Enhancing mitochondrial respiration suppresses tumor promoter TPA-induced PKM2 expression and cell transformation in skin epidermal JB6 cells.
abstract: Differentiated cells primarily metabolize glucose for energy via the tricarboxylic acid cycle and oxidative phosphorylation, but cancer cells thrive on a different mechanism to produce energy, characterized as the Warburg effect, which describes the increased dependence on aerobic glycolysis. The M2 isoform of pyruvate kinase (PKM2), which is responsible for catalyzing the final step of aerobic glycolysis, is highly expressed in cancer cells and may contribute to the Warburg effect. However, whether PKM2 plays a contributing role during early cancer development is unclear. In our studies, we have made an attempt to elucidate the effects of varying mitochondrial respiration substrates on skin cell transformation and expression of PKM2. Tumorigenicity in murine skin epidermal JB6 P+ (promotable) cells was measured in a soft agar assay using 12-O-tetradecanoylphorbol-13-acetate (TPA) as a tumor promoter. We observed a significant reduction in cell transformation upon pretreatment with the mitochondrial respiration substrate succinate or malate/pyruvate. We observed that increased expression and activity of PKM2 in TPA-treated JB6 P+ cells and pretreatment with succinate or malate/pyruvate suppressed the effects. In addition, TPA treatment also induced PKM2 whereas PKM1 expression was suppressed in mouse skin epidermal tissues in vivo. In comparison with JB6 P+ cells, the nonpromotable JB6 P- cells showed no increase in PKM2 expression or activity upon TPA treatment. Knockdown of PKM2 using a siRNA approach significantly reduced skin cell transformation. Thus, our results suggest that PKM2 activation could be an early event and play a contributing role in skin tumorigenesis.
authors.affiliation: Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center-Shreveport, Shreveport, LA 71130, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wittwer
authors.forename: Delira
authors.initials: D
authors.lastname: Robbins
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Sarah
authors.initials: S
authors.lastname: Codarin
authors.forename: Xinggui
authors.initials: X
authors.lastname: Shen
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Kevil
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Huang
authors.forename: Holly
authors.initials: H
authors.lastname: Van Remmen
authors.forename: Arlan
authors.initials: A
authors.lastname: Richardson
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000818:Animals; D019069:Cell Respiration; D002471:Cell Transformation, Neoplastic; D006801:Humans; D008293:Malates / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008928:Mitochondria / Q000378:metabolism*; D020033:Protein Isoforms; D011770:Pyruvate Kinase / Q000378:metabolism*; D019289:Pyruvic Acid / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D012867:Skin / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism*; D019802:Succinic Acid / Q000737:chemistry; D013482:Superoxide Dismutase / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism*
chemical_list: D008293:Malates; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C030298:malic acid; D019289:Pyruvic Acid; D019802:Succinic Acid; D013482:Superoxide Dismutase; D011770:Pyruvate Kinase; D013755:Tetradecanoylphorbol Acetate