title: Hispidulin inhibits proliferation and enhances chemosensitivity of gallbladder cancer cells by targeting HIF-1α.
abstract: Gallbladder cancer (GBC) is an aggressive malignancy of the bile duct, which is associated with a low (5-year) survival and poor prognosis. The transcription factor HIF-1α is implicated in the angiogenesis, cell survival, epithelial mesenchymal transition (EMT) and invasiveness of GBC. In this study, we have investigated the role of HIF-1α in the pathobilogy of GBC and effect of hispidulin on the molecular events controlled by this transcription factor. We observed that hispidulin caused induction of apoptosis, blockade of growth and cell cycle progression in GBC cells. Our results have demonstrated for the first time that hispidulin-exerted anti-tumor effect involved the suppression of HIF-1α signaling. Hispidulin was found to repress the expression of HIF-1α protein dose-dependently without affecting the HIF-1α mRNA expression. In addition, the inhibition of HIF-1α protein synthesis was revealed to be mediated through the activation of AMPK signaling. Hispidulin also sensitized the tumor cells to Gemcitabine and 5-Fluoroucil by down-regulating HIF-1α/P-gp signaling. Given the low cost and exceedingly safe profile, hispidulin appears to be a promising and novel chemosensitizer for GBC treatment.
authors.affiliation: Medical College, Qingdao University, Qingdao, Shandong 266071, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.affiliation: Medical College, Qingdao University, Qingdao, Shandong 266071, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
authors.affiliation: College of Life Sciences, Chongqing Normal University, Chongqing 401331, China. Electronic address: jianjunpeng@126.com.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Peng
authors.affiliation: Medical College, Qingdao University, Qingdao, Shandong 266071, China. Electronic address: hanyt19@126.com.
authors.forename: Yantao
authors.initials: Y
authors.lastname: Han
authors.affiliation: Medical College, Qingdao University, Qingdao, Shandong 266071, China.
authors.forename: Qixiao
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Medical College, Qingdao University, Qingdao, Shandong 266071, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Han
authors.affiliation: Medical College, Qingdao University, Qingdao, Shandong 266071, China.
authors.forename: Chunbo
authors.initials: C
authors.lastname: Wang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D047309:Flavones / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology; D059585:G1 Phase Cell Cycle Checkpoints; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D047309:Flavones; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D003841:Deoxycytidine; C055957:hispidulin; D005472:Fluorouracil; D000093542:Gemcitabine
keywords: Chemosensitivity; Gallbladder cancer; HIF-1α; Hispidulin; P-gp