Novel action modality of the diterpenoid anisomelic acid causes depletion of E6 and E7 viral oncoproteins in HPV-transformed cervical carcinoma cells

Preethy Paul; Senthil Kumar Rajendran; Emilia Peuhu; Ali A Alshatwi; Mohammad A Akbarsha; Sakari Hietanen; John E Eriksson

doi:10.1016/j.bcp.2014.02.011

Novel action modality of the diterpenoid anisomelic acid causes depletion of E6 and E7 viral oncoproteins in HPV-transformed cervical carcinoma cells

Biochem Pharmacol. 2014 May 15;89(2):171-84. doi: 10.1016/j.bcp.2014.02.011. Epub 2014 Feb 22.

Authors

Preethy Paul¹, Senthil Kumar Rajendran², Emilia Peuhu³, Ali A Alshatwi⁴, Mohammad A Akbarsha⁵, Sakari Hietanen⁶, John E Eriksson⁷

Affiliations

¹ Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Biocity, POB 123, FI-20520 Turku, Finland; Department of Biosciences, Åbo Akademi University, Tykistökatu 6, FI-20520 Turku, Finland; Department of Animal Sciences, Bharathidasan University, Tiruchirappalli 620 024, India.
² Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Biocity, POB 123, FI-20520 Turku, Finland; Department of Biosciences, Åbo Akademi University, Tykistökatu 6, FI-20520 Turku, Finland.
³ Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Biocity, POB 123, FI-20520 Turku, Finland.
⁴ Department of Food Sciences and Nutrition, College of Food Sciences and Agriculture, King Saud University, Riyadh 11451, Saudi Arabia.
⁵ Mahatma Gandhi Doerenkamp Center for Alternatives to Use of Animals in Life Science Education, Bharathidasan University, Tiruchirappalli 620 024, India.
⁶ Department of Obstetrics and Gynecology, Turku University Central Hospital, Kiinamyllynk. 4-8, FI-20520 Turku, Finland.
⁷ Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Biocity, POB 123, FI-20520 Turku, Finland; Department of Biosciences, Åbo Akademi University, Tykistökatu 6, FI-20520 Turku, Finland. Electronic address: [email protected].

PMID: 24565908
DOI: 10.1016/j.bcp.2014.02.011

Abstract

Cervical cancer, the second most common malignancy among women, is mainly caused by human papilloma virus (HPV) infection. In HPV-positive cervical cancer cells, the activity of p53 and the induction of p21 are inhibited by the HPV oncoproteins E6 and E7. Therefore, blocking the activity of E6 and E7 would serve as an important therapeutic target in these cancer cells. In this study, anisomelic acid (AA), a natural compound belonging to the same diterpenoid family of bioactive compounds as taxol, was found to deplete the E6 and E7 proteins in HPV-positive cervical cancer cells. Consequently, p53 and the p53-responsive gene, p21, were dramatically induced, leading to G2/M-phase cell cycle arrest. AA-mediated cell cycle arrest and p21 expression were canceled when p53 was down-regulated by p53-shRNA. AA also induced p53-independent intrinsic apoptosis by depletion of the cellular inhibitor of apoptosis protein 2 (cIAP2) whose proteosomal degradation is inhibited by E6. The in ovo chick embryo chorioallantoic membrane (CAM) assay showed that anisomelic acid inhibited the tumor growth of the cervical cancer SiHa cells. AA is revealed to hold a novel action modality based on specific targeting of the HPV oncoproteins, which restores p53-mediated growth arrest and induces apoptosis by terminating E6-mediated cIAP2 stabilization.

Keywords: Anisomelic acid; Apoptosis; Cell cycle arrest; Cervical cancer; Human papilloma virus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chick Embryo
Diterpenes / pharmacology*
Diterpenes / therapeutic use*
Dose-Response Relationship, Drug
Female
HeLa Cells
Human papillomavirus 6 / drug effects
Human papillomavirus 6 / metabolism*
Humans
MCF-7 Cells
Papillomavirus E7 Proteins / antagonists & inhibitors*
Papillomavirus E7 Proteins / metabolism
Uterine Cervical Neoplasms / drug therapy
Uterine Cervical Neoplasms / virology*

Substances

Diterpenes
Papillomavirus E7 Proteins