Degradation of mutant p53H175 protein by Zn(II) through autophagy

Garufi, Alessia; Pucci, Daniela; D’Orazi, Valerio; Cirone, Mara; Bossi, Gianluca; Avantaggiati, Maria Laura; D’Orazi, Gabriella

doi:10.1038/cddis.2014.217

Cited by 86 publications

(86 citation statements)

References 55 publications

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“…Small-molecule compounds targeting mutp53 have been recently used on the basis of putative conformational changes within mutp53 proteins to restore wild-type p53, or protein degradation through autophagy, as also demonstrated by our studies [17, 18]. Therefore, we investigated whether CPS could trigger mutp53 protein clearing.…”

Section: Resultsmentioning

confidence: 80%

Reactivation of mutant p53 by capsaicin, the major constituent of peppers

Garufi

Pistritto

Cirone

et al. 2016

J Exp Clin Cancer Res

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BackgroundMutations in the p53 oncosuppressor gene are highly frequent in human cancers. These alterations are mainly point mutations in the DNA binding domain of p53 and disable p53 from transactivating target genes devoted to anticancer activity. Mutant p53 proteins are usually more stable than wild-type p53 and may not only impair wild-type p53 activity but also acquire pro-oncogenic functions. Therefore, targeting mutant p53 to clear the hyperstable proteins or change p53 conformation to reactivate wild-type p53 protein functions is a powerful anticancer strategy. Several small molecules have been tested for p53 reactivation in mutant p53-carrying cells while studies exploiting the effect of natural compounds are limited. Capsaicin (CPS) is the major constituent of peppers and show antitumor activity by targeting several molecular pathway, however, its effect on mutant p53 reactivation has not been assessed yet. In this study we aimed at investigating whether mutant p53 could be a new target of capsaicin-induced cell death and the underlying mechanisms.Methodsp53 levels were analysed by western blot upon capsaicin treatment in the presence of the autophagy inhibitor chloroquine. The mutant p53 reactivation was evaluated by chromatin-immunoprecipitation (ChIP) assay and semi-quantitative RT-PCR analyses of wild-type p53 target genes. The specific wild-type p53 activation was determined by using the inhibitor of p53 transactivation function, pifithrin-α and siRNA for p53.ResultsHere, we show that capsaicin induced autophagy that was, at least in part, responsible of mutant p53 protein degradation. Abrogation of mutant p53 by capsaicin restored wild-type p53 activities over mutant p53 functions, contributing to cancer cell death. Similar effects were confirmed in cancer cells bearing tumor-associated p53 mutations and in H1299 (p53 null) with overexpressed p53R175H and p53R273H mutant proteins.ConclusionThese findings demonstrate for the first time that capsaicin may reduce mutant p53 levels and reactivate wild-type p53 protein in mutant p53-carrying cells and the p53 reactivation contributes to capsaicin-induced cell death.

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Section: Resultsmentioning

confidence: 80%

Reactivation of mutant p53 by capsaicin, the major constituent of peppers

Garufi

Pistritto

Cirone

et al. 2016

J Exp Clin Cancer Res

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“…CHIP has been shown to degrade wild-type p53 via the UPS [16]. Besides, Zn(II)curcumin also degrades mutant p53 via wild-type p53mediated autophagy [20]. Besides, Zn(II)curcumin also degrades mutant p53 via wild-type p53mediated autophagy [20].…”

Section: Discussionmentioning

confidence: 99%

“…Glucose starvation also induces mutant p53 protein degradation through autophagy, which renders tumor cells hypersensitive to autophagic cell death [19]. Besides, Zn(II)-curcumin displays a novel mechanism in the degradation of mutant p53, involving induction of mutant p53 degradation via wild-type p53-mediated autophagy [20]. However, the molecular mechanisms and cellular players involved in autophagic degradation of mutant p53 are still unknown.…”

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confidence: 99%

CHIP promotes autophagy‐mediated degradation of aggregating mutant p53 in hypoxic conditions

Maan

Pati

2018

The FEBS Journal

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Tumor suppressor protein p53 aggregates in the hypoxic core of solid tumors. C terminus of Hsc70-interacting protein (CHIP) displays chaperone as well as E3 ligase activities in both stabilizing and degrading wild-type and mutant p53. In this study, we have discovered that CHIP selectively degrades aggregating mutant p53 under both normal and hypoxic conditions. Silencing of CHIP alleviates degradation of aggregating mutant p53 in both normoxia and hypoxia, but has no significant effect on the level of nonaggregating mutant p53. Although both U-box and TPR domains of CHIP are responsible for p53 degradation, the U-box domain selectively binds to aggregating mutant p53, whereas the TPR domain interacts with nonaggregating mutant p53. The degradation of mutant p53 by CHIP is shown to be via autophagy through K63-linked polyubiquitination. Both in normoxia and under physiological hypoxia, the level of aggregating mutant p53 in the presence of CHIP was reduced threefold, whereas under serum starvation, it was reduced fivefold. Interestingly, both wild-type and mutant p53 interact with and stabilize CHIP at the post-translational level, suggesting a chaperone synergy between p53 and CHIP. This finding may have strong therapeutic significance via selective degradation of oncogenic mutant p53 in regressing hypoxic tumors.

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“…In some experiments, BC3 were treated with Thapsigargin (5 μM) for 24 hrs. To evaluate the role of autophagy in viral replication, BC3 and Raji cell lines were cultured with bortezomib (20 μM) (Santa Cruz Biotechnology Inc.) in the presence or in the absence of chloroquine (10 μM) (Sigma Aldrich) or with 3-Methyladenine (3-MA) (5 mM) (Santa Cruz Biotechnology Inc.) for 24 hrs 32,33 . To further investigate autophagy, siRNA ATG5 experiments were performed on the same cell line, as previously reported 15 .…”

Section: Methodsmentioning

confidence: 99%

Bortezomib promotes KHSV and EBV lytic cycle by activating JNK and autophagy

Granato

Romeo

Tiano

et al. 2017

Sci Rep

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KSHV and EBV are gammaherpesviruses strictly linked to human cancers. Even if the majority of cancer cells harbor a latent infection, the few cells that undergo viral replication may contribute to the pathogenesis and maintenance of the virus-associated malignancies. Cytotoxic drugs used for the therapies of cancers harboring virus-infection often have, as side effect, the activation of viral lytic cycle. Therefore it is important to investigate whether they affect viral reactivation and understand the underlying mechanisms involved. In this study, we found that proteasome inhibitor bortezomib, a cytotoxic drug that efficiently target gammaherpesvirus-associated B cell lymphomas, triggered KSHV or EBV viral lytic cycle by activating JNK, in the course of ER stress, and inducing autophagy. These results suggest that the manipulation of these pathways could limit viral spread and improve the outcome of bortezomib treatment in patients affected by gammaherpesvirus-associated lymphomas.

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Degradation of mutant p53H175 protein by Zn(II) through autophagy

Cited by 86 publications

References 55 publications

Reactivation of mutant p53 by capsaicin, the major constituent of peppers

Reactivation of mutant p53 by capsaicin, the major constituent of peppers

CHIP promotes autophagy‐mediated degradation of aggregating mutant p53 in hypoxic conditions

Bortezomib promotes KHSV and EBV lytic cycle by activating JNK and autophagy

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