title: Baicalein reverses hypoxia-induced 5-FU resistance in gastric cancer AGS cells through suppression of glycolysis and the PTEN/Akt/HIF-1α signaling pathway.
abstract: Cancer cells can survive under hypoxia by metabolic reprogramming to achieve a high level of glycolysis, which contributes to the development of chemoresistance. Therefore, inhibition of glycolysis would be a novel strategy for overcoming hypoxia‑induced drug resistance. Baicalein, a flavonoid derived from the root of Scutellaria baicalensis, has been reported to exert strong antitumor activity toward various types of cancer. In the present study, we evaluated the effect of baicalein on hypoxia-induced 5-fluorouracil (5-FU) resistance in gastric cancer AGS cells and investigated the possible molecular mechanisms. We found that baicalein increased the sensitivity of AGS cells to 5-FU treatment under hypoxia. In addition, the hypoxia-enhanced glycolytic flux and expression of several critical glycolysis-associated enzymes (HK2, LDH-A and PDK1) in the AGS cells were suppressed by baicalein. Furthermore, baicalein inhibited hypoxia-induced Akt phosphorylation by promoting PTEN accumulation, thereby attenuating hypoxia-inducible factor-1α (HIF-1α) expression in AGS cells. These results together suggest that inhibition of glycolysis via regulation of the PTEN/Akt/HIF-1α signaling pathway may be one of the mechanisms whereby baicalein reverses 5-FU resistance in cancer cells under hypoxia.
authors.affiliation: Department of Gastroenterology, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China.
authors.forename: Fenglin
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China.
authors.forename: Mingkai
authors.initials: M
authors.lastname: Zhuang
authors.affiliation: College of Union Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China.
authors.forename: Canmei
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Academy of Integrative Medicine Biomedical Research Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350001, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Gastroenterology, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China.
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China.
authors.forename: Jianying
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Huang
mesh_terms: D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D044950:Flavanones / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
chemical_list: D044950:Flavanones; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019344:Lactic Acid; C006680:baicalein; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D005472:Fluorouracil