BAG3 down-modulation sensitizes HPV18(+) HeLa cells to PEITC-induced apoptosis and restores p53

Roberta Cotugno; Anna Basile; Elena Romano; Dario Gallotta; Maria Antonietta Belisario

doi:10.1016/j.canlet.2014.08.022

BAG3 down-modulation sensitizes HPV18(+) HeLa cells to PEITC-induced apoptosis and restores p53

Cancer Lett. 2014 Nov 28;354(2):263-71. doi: 10.1016/j.canlet.2014.08.022. Epub 2014 Aug 28.

Authors

Roberta Cotugno¹, Anna Basile¹, Elena Romano¹, Dario Gallotta¹, Maria Antonietta Belisario²

Affiliations

¹ Department of Pharmacy, University of Salerno, Via Giovanni Paolo II n.132, Fisciano, 84084, Salerno, Italy.
² Department of Pharmacy, University of Salerno, Via Giovanni Paolo II n.132, Fisciano, 84084, Salerno, Italy. Electronic address: [email protected].

Abstract

BAG3 is a multi-functional component of tumor cell pro-survival machinery, and its biological functions have been largely associated to proteasome system. Here, we show that BAG3 down-modulation resulted in reduced cell viability and enhanced PEITC-induced apoptosis largely more extensively in HeLa (HPV18(+)) rather than in C33A (HPV(-)) cervical carcinoma cell lines. Moreover, we demonstrate that BAG3 suppression led to a decrease of viral E6 oncoprotein and a concomitant recovery of p53 tumor suppressor, the best recognized target of E6 for proteasome degradation. E6 and p53 expression were modulated at protein level, since their respective mRNAs were unaffected. Taken together our findings reveal a novel role for BAG3 as host protein contributing to HPV18 E6-activated pro-survival strategies, and suggest a possible relevance of its expression levels in drug/radiotherapy-resistance of HPV18-bearing cervical carcinomas.

Keywords: BAG3; E6; HPV18; HeLa cells; PEITC; p53.

Publication types

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

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Apoptosis / drug effects
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
DNA-Binding Proteins / metabolism
Down-Regulation
Female
HeLa Cells
Human papillomavirus 18
Humans
Isothiocyanates / pharmacology*
Oncogene Proteins, Viral / metabolism
RNA, Small Interfering / administration & dosage
RNA, Small Interfering / genetics
Transfection
Tumor Suppressor Protein p53 / metabolism*
Ubiquitin-Protein Ligases / metabolism
Uterine Cervical Neoplasms / drug therapy*
Uterine Cervical Neoplasms / metabolism
Uterine Cervical Neoplasms / pathology
Uterine Cervical Neoplasms / virology*

Substances

Adaptor Proteins, Signal Transducing
Apoptosis Regulatory Proteins
BAG3 protein, human
DNA-Binding Proteins
E6 protein, Human papillomavirus type 18
Isothiocyanates
Oncogene Proteins, Viral
RNA, Small Interfering
TP53 protein, human
Tumor Suppressor Protein p53
phenethyl isothiocyanate
UBE3A protein, human
Ubiquitin-Protein Ligases