[논문]Suppression of HIF-1α accumulation by betulinic acid through proteasome activation in hypoxic cervical cancer

Kim, Hwee-Jin; Cho, Hyun-Soo; Ban, Hyun Seung; Nakamura, Hiroyuki

doi:10.1016/j.bbrc.2020.01.031

[해외논문] Suppression of HIF-1α accumulation by betulinic acid through proteasome activation in hypoxic cervical cancer

Biochemical and biophysical research communications, v.523 no.3, 2020년, pp.726 - 732

Kim, Hwee-Jin (Korea Research Institute of Bioscience and Biotechnology) , Cho, Hyun-Soo (Korea Research Institute of Bioscience and Biotechnology) , Ban, Hyun Seung (Korea Research Institute of Bioscience and Biotechnology) , Nakamura, Hiroyuki (Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology)

Abstract ▼ AI-Helper

Abstract 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. Highlights Betulinic acid (BA) suppresses hypoxia-induced accumulation of HIF-1α. BA suppresses expression of HIF target genes VEGF, GLUT1, and PDK1 in HeLa cells. HIF was inhibited by direct activation of proteasome β1, β2, and β5 activity. BA shows potential as an anticancer agent for regulating the HIF signaling pathway.

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