Ursolic acid inhibits proliferation and reverses drug resistance of ovarian cancer stem cells by downregulating ABCG2 through suppressing the expression of hypoxia-inducible factor-1α in vitro

• Published in: Oncology reports Vol. 36; no. 1; pp. 428 - 440
• Main Authors: WANG, WEN-JING, SUI, HUA, QI, CONG, LI, QI, ZHANG, JIE, WU, SHAO-FEI, MEI, MING-ZHU, LU, YING-YU, WAN, YI-TING, CHANG, HANNAH, GUO, PIAO-TING
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.07.2016; Spandidos Publications UK Ltd
• Subjects: ABCG2; Acids; Apoptosis; ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics; Basic Helix-Loop-Helix Transcription Factors - genetics; Cell culture; Cell Hypoxia - drug effects; Cell Hypoxia - genetics; Cell Line, Tumor; Cell Proliferation - drug effects; Childrens health; Chinese medicine; Cisplatin - pharmacology; Down-Regulation - drug effects; Down-Regulation - genetics; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; drug resistant; Female; Flow cytometry; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; HIF-1α; Hospitals; Humans; Hypoxia; Mortality; Neoplasm Proteins - genetics; Neoplastic Stem Cells - drug effects; Ovarian cancer; ovarian cancer stem cells; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Phosphatidylinositol 3-Kinases - genetics; Proteins; Proto-Oncogene Proteins c-akt - genetics; RNA, Small Interfering - genetics; Rodents; Signal Transduction - drug effects; Signal Transduction - genetics; Stem cells; Triterpenes - pharmacology; Tumors; Ursolic Acid; United States > US
• ISSN: 1021-335X; 1791-2431
• DOI: 10.3892/or.2016.4813

Hypoxia in tumors is closely related to drug resistance. It has not been verified whether hypoxia-inducible factor-1α (HIF-1α) or ABCG2 is related to hypoxia-induced resistance. Ursolic acid (UA), when used in combination with cisplatin can significantly increase the sensitivity of ovarian cancer stem cells (CSCs) to cisplatin, but the exact mechanism is unknown. The cell growth inhibitory rate of cisplatin under different conditions was evaluated using Cell Counting Kit-8 (CCK-8) in adherence and sphere cells (SKOV3, A2780, and HEY). The expression of HIF-1α and ABCG2 was tested using quantitative PCR, western blotting, and immunofluorescence under different culture conditions and treated with UA. Knockdown of HIF-1α by shRNA and LY294002 was used to inhibit the activity of PI3K/Akt pathway. Ovarian CSCs express stemness-related genes and drug resistance significantly higher than normal adherent cells. Under hypoxic conditions, the ovarian CSCs grew faster and were more drug resistant than under normoxia. UA could inhibit proliferation and reverse the drug resistance of ovarian CSC by suppressing ABCG2 and HIF-1α under different culture conditions. HIF-1α inhibitor YC-1 combined with UA suppressed the stemness genes and ABCG2 under hypoxic condition. The PI3K/Akt signaling pathway activation plays an important functional role in UA-induced downregulation of HIF-1α and reduction of ABCG2. UA inhibits the proliferation and reversal of drug resistance in ovarian CSCs by suppressing the expression of downregulation of HIF-1α and ABCG2.