期刊
MOLECULAR NUTRITION & FOOD RESEARCH
卷 60, 期 6, 页码 1482-1500出版社
WILEY
DOI: 10.1002/mnfr.201500977
关键词
Apoptosis; Cell cycle arrest; Colorectal cancer cell; Cyclooxygenase-2; c-myc; Sirtuin 1
资金
- National Center for Research Resources [2G12RR003061-26]
- National Institute on Minority Health and Health Disparities [8G12MD7601-27]
Scope: Physalis peruviana (Solanaceae) is used for culinary and medicinal purposes. We currently report withanolides, isolated from P. peruviana, inhibit the growth of colon cancer monolayer and spheroid cultures. A detailed mechanistic evaluation was performed with 4 beta-hydroxywithanolide E (4HWE). Methods and results: Treatment of HT-29 cells with low concentrations of 4HWE inhibited growth while enhancing levels of p21Waf1/Cip1 and reducing levels of several cell cycle-related proteins. Apoptosis was induced at higher concentrations. In addition, 4HWE treatment downregulated the levels of Hsp90 client proteins. Nuclear sirtuin 1 (SIRT1) was increased and histone H3 acetylated at lysine 9 was decreased. An additional consequence of SIRT1 elevation in the nucleus may be inhibition of c-Jun activity. The expression of 21 genes was altered, including downregulation of PTGS2, and this correlated with reduced protein levels of cyclooxygenase-2 (COX-2). Overall, efficacious induction of G0/G1 cell cycle arrest at low concentrations, and induction of apoptosis at higher concentrations are interesting 4HWE-mediated phenomena that are accompanied by a complex array of molecular events. Conclusion: Considering the worldwide prevalence of colon cancer, and the unique mode of actionmediated by 4HWE, it is reasonable to investigate additional mechanistic details and the potential utility of this compound.
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