title: Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer.
abstract: Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo In addition, we demonstrate for the first time that TGFβ mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGFβ signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGFβ pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGFβ/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, and Departments of Genetics, Cell Biology, and Anatomy.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: the Department of Cell Biology, Third Military Medical University, Chongqing 400038, China, and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, and.
authors.forename: Liying
authors.initials: L
authors.lastname: Geng
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, and Departments of Genetics, Cell Biology, and Anatomy.
authors.forename: Haowei
authors.initials: H
authors.lastname: Yi
authors.affiliation: Department of Oncology, Dalian Central Hospital, Dalian 116033, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huo
authors.affiliation: Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Talmon
authors.affiliation: Departments of Genetics, Cell Biology, and Anatomy.
authors.forename: Yeong C
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Departments of Genetics, Cell Biology, and Anatomy.
authors.forename: San Ming
authors.initials: SM
authors.lastname: Wang
authors.affiliation: From the Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, and Departments of Genetics, Cell Biology, and Anatomy, Biochemistry and Molecular Biology, and jjwang@unmc.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D051899:Smad2 Protein / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000595707:BCL2 protein, human; D009944:Organoplatinum Compounds; C000631432:PDK4 protein, human; C000631439:Pdk4 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D000077150:Oxaliplatin; D017346:Protein Serine-Threonine Kinases; D005472:Fluorouracil
keywords: 5-FU; B cell lymphoma 2 (Bcl-2); DCA; TGFβ; apoptosis; colorectal cancer; drug resistance; pyruvate dehydrogenase kinase (PDC kinase); survivin