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

Abstract

a b s t r a c tThe 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.

The dissociation of the Hsp60/pro-Caspase-3 complex by bis(pyridyl)oxadiazole copper complex ( CubipyOXA ) leads to cell death in NCI-H292 cancer cells

“…These findings suggest that the reduction of Hsp60 levels might have various causes, as it has been already demonstrated, in which Hsp60 could be tagged by post-translational modifications, such as hyperacetylation and ubiquitination. This could regulate the degradation of the chaperone by the ubiquitin-proteosome system [12,55]. Otherwise, the post-translational modifications could constitute a signal for extracellular secretion through the lipid raft pathway [11,49,56].…”

“…The function of extracellular Hsp60 is still under discussion. For instance, it may mediate interactions with the immune cells and other body tissues and alter the tumor microenvironment [11,12,55,57].…”

Multifaceted Health Benefits of Mangifera indica L. (Mango): The Inestimable Value of Orchards Recently Planted in Sicilian Rural Areas

“…The anti-scavenging activity of these cultivars was positively correlated with both ascorbic acid and total polyphenol contents [30], albeit the authors did not explore the biochemical mechanism responsible for the observed effects. In this scenario, we recently started to explore the antioxidant and anti-aging properties of Sicilian mango extracts exploiting our knowledge in the study of oxidative stress and cell death induction in tumour systems [31,32,33,34,35,36,37]. Using fruit extract from the Kensington Pride cultivar grown and widely spread in Balestrate (Palermo) and other Sicilian rural areas, our preliminary results provided evidence that exocarp, mesocarp, and endocarp of mango can efficaciously counteract oxidative damage caused by ROS.…”

Curcumin Affects HSP60 Folding Activity and Levels in Neuroblastoma Cells

“…The treatment with a copper compound with cytotoxic properties induced the decrease in the HSP60 levels, the separation of the complex HSP60/pC3, and consequently, the C3 activation of the caspase pathway associated with a tumor-cell growth arrest [50]. In addition, we found that the antitumor agent doxorubicin acted on the NCI-H292 cell line by lowering the levels of intracellular HSP60 and determining the HSP60 acetylation, which seems to be responsible for the disruption of Hsp60/p53 complex and the activation of replicative senescence, probably via p53-p21 pathway [51]. Our previous findings reported that high levels of HSP60 may have an anti-apoptotic and cytoprotective role in cancer [15,[50][51][52].…”