Doxorubicin anti-tumor mechanisms include Hsp60 post-translational modifications leading to the Hsp60/p53 complex dissociation and instauration of replicative senescence.
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.
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.
Antonella
A
Marino Gammazza
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
Claudia
C
Campanella
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
Rosario
R
Barone
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
Celeste
C
Caruso Bavisotto
Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland.
Magdalena
M
Gorska
Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland.
Michal
M
Wozniak
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy.
Francesco
F
Carini
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
Francesco
F
Cappello
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo, Palermo, Italy.
Antonella
A
D'Anneo
Department of Experimental Biomedicine and Clinical Neurosciences, Laboratory of Biochemistry, University of Palermo, Palermo, Italy.
Marianna
M
Lauricella
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy.
Giovanni
G
Zummo
Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore, Baltimore, MD, USA; IMET, Columbus Center, Baltimore, MD, USA.
Everly
E
Conway de Macario
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.
Alberto J L
AJ
Macario
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
Valentina
V
Di Felice
D000107:Acetylation; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018277:Carcinoma, Mucoepidermoid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D018834:Chaperonin 60 / Q000235:genetics / Q000378:metabolism*; D018833:Chaperonins / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D059748:Proteolysis; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
D000903:Antibiotics, Antineoplastic; C493956:CDKN1A protein, human; D018834:Chaperonin 60; D050759:Cyclin-Dependent Kinase Inhibitor p21; C468783:H2AX protein, human; C060293:HSPD1 protein, human; D006657:Histones; D024101:Mitochondrial Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D018833:Chaperonins
Acetylation; Doxorubicin; Hsp60; Replicative senescence; Ubiquitination; p53