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Induction of cell cycle arrest and apoptosis with downregulation of Hsp90 client proteins and histone modification by 4β‐hydroxywithanolide E isolated from Physalis peruviana
Author(s) -
Park EunJung,
SangNgern Mayuramas,
Chang Leng Chee,
Pezzuto John M.
Publication year - 2016
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201500977
Subject(s) - apoptosis , downregulation and upregulation , cell cycle checkpoint , cell cycle , cell growth , acetylation , histone , cell , sirtuin , biology , microbiology and biotechnology , chemistry , biochemistry , gene
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 4β‐hydroxywithanolide E (4HWE). Methods and results Treatment of HT‐29 cells with low concentrations of 4HWE inhibited growth while enhancing levels of p21 Waf1/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 action mediated by 4HWE, it is reasonable to investigate additional mechanistic details and the potential utility of this compound.