Format

Send to

Choose Destination
Cancer Lett. 2017 Jan 28;385:75-86. doi: 10.1016/j.canlet.2016.10.045. Epub 2016 Nov 9.

Doxorubicin anti-tumor mechanisms include Hsp60 post-translational modifications leading to the Hsp60/p53 complex dissociation and instauration of replicative senescence.

Author information

1
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy. Electronic address: antonella.marino@hotmail.it.
2
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
3
Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland.
4
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy.
5
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo, Palermo, Italy.
6
Department of Experimental Biomedicine and Clinical Neurosciences, Laboratory of Biochemistry, University of Palermo, Palermo, Italy.
7
Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore, Baltimore, MD, USA; IMET, Columbus Center, Baltimore, MD, USA.
8
Euro-Mediterranean Institute of Science and Technology, Palermo, Italy; Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore, Baltimore, MD, USA; IMET, Columbus Center, Baltimore, MD, USA.

Abstract

The chaperone Hsp60 is pro-carcinogenic in certain tumor types by interfering with apoptosis and with tumor cell death. In these tumors, it is not yet known whether doxorubicin anti-tumor effects include a blockage of the pro-carcinogenic action of Hsp60. We found a doxorubicin dose-dependent viability reduction in a human lung mucoepidermoid cell line that was paralleled by the appearance of cell senescence markers. Concomitantly, intracellular Hsp60 levels decreased while its acetylation levels increased. The data suggest that Hsp60 acetylation interferes with the formation of the Hsp60/p53 complex and/or promote its dissociation, both causing an increase in the levels of free p53, which can then activate the p53-dependent pathway toward cell senescence. On the other hand, acetylated Hsp60 is ubiquitinated and degraded and, thus, the anti-apoptotic effect of the chaperonin is abolished with subsequent tumor cell death. Our findings could help in the elucidation of the molecular mechanisms by which doxorubicin counteracts carcinogenesis and, consequently, it would open new roads for the development of cancer treatment protocols targeting Hsp60.

KEYWORDS:

Acetylation; Doxorubicin; Hsp60; Replicative senescence; Ubiquitination; p53

PMID:
27836734
DOI:
10.1016/j.canlet.2016.10.045
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center