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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 information

Affiliations

  • 1. Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, Hilo, HI, USA.
      Authors
    • Park EJ 1
    • Sang-Ngern M 1
    • Chang LC 1
    • Pezzuto JM 1
    (4 authors)

ORCIDs linked to this article

Molecular Nutrition & Food Research, 11 May 2016, 60(6):1482-1500
https://doi.org/10.1002/mnfr.201500977 PMID: 27006100 

Abstract 

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.

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Read article at publisher's site: https://doi.org/10.1002/mnfr.201500977

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Funding 

Funders who supported this work.

NCRR NIH HHS (1)

NIMHD NIH HHS (1)

National Center for Research Resources (1)

National Institute on Minority Health and Health Disparities