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: Hui Gao, Jing Xie, Jianjun Peng, Yantao Han, Qixiao Jiang, Mei Han, Chunbo Wang
• Journal: Experimental cell research (Exp Cell Res) Vol. 332 Issue 2 Pg. 236-46 (Mar 15 2015) ISSN: 1090-2422 [Electronic] United States
• PMID: 25499970 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Flavones
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Deoxycytidine
• hispidulin
• Fluorouracil
• Gemcitabine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm
• Drug Synergism
• Female
• Flavones (pharmacology)
• Fluorouracil (pharmacology)
• G1 Phase Cell Cycle Checkpoints
• Gallbladder Neoplasms (drug therapy, genetics, metabolism, pathology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, metabolism)
• Mice, Inbred BALB C
• Mice, Nude
• Signal Transduction
• Transcriptional Activation (drug effects)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays
• Gemcitabine