Veratramine Inhibits the Cell Cycle Progression, Migration, and Invasion via ATM/ATR Pathway in Androgen-Independent Prostate Cancer

Hee Yeon Kim, Seoung Woo Lee, Seong Kyoon Choi, Janbolat Ashim, Wansoo Kim, Su Min Beak, Jin Kyu Park, Jee Eun Han, Gil Jae Cho, Zae Young Ryoo, Jain Jeong, Yong Ho Lee, Hyohoon Jeong, Wookyung Yu, Song Park

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Prostate cancer (PC) is the second leading cause of cancer-related death among men. Treatment of PC becomes difficult after progression because PC that used to be androgen-dependent becomes androgen-independent prostate cancer (AIPC). Veratramine, an alkaloid extracted from the root of the Veratrum genus, has recently been reported to have anticancer effects that work against various cancers; however, its anticancer effects and the underlying mechanism of action in PC remain unknown. We investigated the anticancer effects of veratramine on AIPC using PC3 and DU145 cell lines, as well as a xenograft mouse model. The antitumor effects of veratramine were evaluated using the CCK-8, anchorage-independent colony formation, trans-well, wound healing assays, and flow cytometry in AIPC cell lines. Microarray and proteomics analyses were performed to investigate the differentially expressed genes and proteins induced by veratramine in AIPC cells. A xenograft mouse model was used to confirm the therapeutic response and in vivo efficacy of veratramine. Veratramine dose dependently reduced the proliferation of cancer cells both in vitro and in vivo. Moreover, veratramine treatment effectively suppressed the migration and invasion of PC cells. The immunoblot analysis revealed that veratramine significantly downregulated Cdk4/6 and cyclin D1 via the ATM/ATR and Akt pathways, both of which induce a DNA damage response that eventually leads to G1 phase arrest. In this study, we discovered that veratramine exerted antitumor effects on AIPC cells. We demonstrated that veratramine significantly inhibited the proliferation of cancer cells via G0/G1 phase arrest induced by the ATM/ATR and Akt pathways. These results suggest that veratramine is a promising natural therapeutic agent for AIPC.

Original languageEnglish
Pages (from-to)1309-1333
Number of pages25
JournalAmerican Journal of Chinese Medicine
Volume51
Issue number5
DOIs
StatePublished - 2023

Keywords

  • Androgen-Independent Prostate Cancer
  • Anticancer
  • Cell Cycle Arrest
  • Phytomedicine
  • Veratramine
  • Veratrum Genus

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