Suppression of HIF-1α accumulation by betulinic acid through proteasome activation in hypoxic cervical cancer.
Betulinic acid (BA) exhibits various biological activities such as anti-bacterial, anti-inflammatory, anti-human papilloma virus (HPV), and anti-cancer activities. HPV infection is associated with a high risk of cervical cancer, which is the leading cause of deaths among women worldwide. Therefore, BA is an attractive therapeutic agent for treating cervical cancer. In this study, we investigated the role of BA in regulating the hypoxia-mediated response in HeLa cells and clarified the underlying mechanism of action. We found that BA inhibited the hypoxia-induced accumulation of HIF-1α without affecting HIF-1α mRNA levels and suppressed the expression of HIF target genes, including VEGF, GLUT1, and PDK1 in HeLa cells. Additionally, BA enhanced the β1, β2, and β5 activities of the proteasome, which resulted in reduced levels of ubiquitinated proteins and HIF-1α protein in HeLa cells. However, BA treatment did not affect the deubiquitinase enzyme activity in HeLa cells. These results indicate that inhibition of HIF-1α accumulation by BA is mediated by activation of the proteasome, and BA is a potential anticancer agent for the regulation of the HIF signaling pathway.
['Kim|Hwee-Jin|HJ|', 'Cho|Hyun-Soo|HS|', 'Ban|Hyun Seung|HS|', 'Nakamura|Hiroyuki|H|']
D000972:Antineoplastic Agents, Phytogenic D004789:Enzyme Activation D005260:Female D006367:HeLa Cells D006801:Humans D051795:Hypoxia-Inducible Factor 1, alpha Subunit D053978:Pentacyclic Triterpenes D046988:Proteasome Endopeptidase Complex D014315:Triterpenes D000072258:Tumor Hypoxia D002583:Uterine Cervical Neoplasms
Betulinic acid Proteasome Cancer Ubiquitination Hypoxia Hypoxia-inducible factor