title: Dichloroacetate attenuates hypoxia-induced resistance to 5-fluorouracil in gastric cancer through the regulation of glucose metabolism.
abstract: In this study, we investigated whether gastric cancer with hypoxia-induced resistance to 5-fluorouracil (5-FU) could be re-sensitized following treatment with low-dose dichloroacetate (DCA), an inhibitor of the glycolytic pathway. The expression profiles of hypoxia-inducible factor-1α (HIF-1α) and pyruvate dehydrogenase kinase-1 (PDK-1) were analyzed in tissues from 10 patients with gastric cancer who had different responses to adjuvant 5-FU treatment. For the in vitro assays, cell viability and apoptosis were evaluated with and without treatment with 20mM DCA in the AGS and MKN45 cell lines, as well as in PDK1 knockdown cell lines. The expression levels of HIF-1α and PDK-1 were both elevated in the tumor tissues relative to the normal gastric tissues of most patients who showed recurrence after adjuvant 5-FU treatment. Cellular viability tests showed that these cell lines had a lower sensitivity to 5-FU under hypoxic conditions compared to normoxic conditions. Moreover, the addition of 20mM DCA only increased the sensitivity of these cells to 5-FU under hypoxic conditions, and the resistance to 5-FU under hypoxia was also attenuated in PDK1 knockdown cell lines. In conclusion, DCA treatment was able to re-sensitize gastric cancer cells with hypoxia-induced resistance to 5-FU through the alteration of glucose metabolism.
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon 443-749, Republic of Korea; Institute for Gastric Cancer Mechanism, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xuan
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon 443-749, Republic of Korea; Institute for Gastric Cancer Mechanism, Ajou University School of Medicine, Suwon 443-749, Republic of Korea. Electronic address: hhcmc75@naver.com.
authors.forename: Hoon
authors.initials: H
authors.lastname: Hur
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon 443-749, Republic of Korea; Institute for Gastric Cancer Mechanism, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.
authors.forename: In-Hye
authors.initials: IH
authors.lastname: Ham
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon 443-749, Republic of Korea; Institute for Gastric Cancer Mechanism, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.
authors.forename: Jisoo
authors.initials: J
authors.lastname: Yun
authors.affiliation: Department of Molecular Science and Technology, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.
authors.forename: Ji-Yoon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Medical Research Institute, Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Shim
authors.affiliation: Department of Pathology, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.
authors.forename: Young Bae
authors.initials: YB
authors.lastname: Kim
authors.affiliation: Institute for Gastric Cancer Mechanism, Ajou University School of Medicine, Suwon 443-749, Republic of Korea; Department of Molecular Science and Technology, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.
authors.forename: Gwang
authors.initials: G
authors.lastname: Lee
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon 443-749, Republic of Korea; Institute for Gastric Cancer Mechanism, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.
authors.forename: Sang-Uk
authors.initials: SU
authors.lastname: Han
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon 443-749, Republic of Korea.
authors.forename: Yong Kwan
authors.initials: YK
authors.lastname: Cho
mesh_terms: D000328:Adult; D000368:Aged; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D003999:Dichloroacetic Acid; D005947:Glucose; D005472:Fluorouracil
keywords: 5-Flurouracil; Chemoresistance; Dichloroacetate; Gastric neoplasm; Hypoxia; Pyruvate dehydrogenase kinase