Mutant p53 as a Regulator and Target of Autophagy

Shi, Yong; Norberg, Erik; Vakifahmetoglu-Norberg, Helin

doi:10.3389/fonc.2020.607149

Cited by 39 publications

(39 citation statements)

References 183 publications

(257 reference statements)

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“…Autophagy inhibition can be viewed as a p53 GOF that promotes tumor progression by reducing mutp53 degradation via the autophagy pathway [ 97 ]. The canonical AMPK/mTOR pathway is regarded as the core signaling cascade of mutp53-mediated suppression of autophagy [ 98 ]. Pharmacological induction of autophagy by mTOR inhibition or AMPK activation has been shown to have potential therapeutic value, and the activation of autophagy induced by mutp53 makes cancer cells more sensitive to the mTOR inhibitor everolimus, especially in cancers with p53 mutations [ 96 ].…”

Section: Synthetic Lethality With P53: a Strategy That Makes P53 Druggablementioning

confidence: 99%

Targeting mutant p53 for cancer therapy: direct and indirect strategies

et al. 2021

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TP53 is a critical tumor-suppressor gene that is mutated in more than half of all human cancers. Mutations in TP53 not only impair its antitumor activity, but also confer mutant p53 protein oncogenic properties. The p53-targeted therapy approach began with the identification of compounds capable of restoring/reactivating wild-type p53 functions or eliminating mutant p53. Treatments that directly target mutant p53 are extremely structure and drug-species-dependent. Due to the mutation of wild-type p53, multiple survival pathways that are normally maintained by wild-type p53 are disrupted, necessitating the activation of compensatory genes or pathways to promote cancer cell survival. Additionally, because the oncogenic functions of mutant p53 contribute to cancer proliferation and metastasis, targeting the signaling pathways altered by p53 mutation appears to be an attractive strategy. Synthetic lethality implies that while disruption of either gene alone is permissible among two genes with synthetic lethal interactions, complete disruption of both genes results in cell death. Thus, rather than directly targeting p53, exploiting mutant p53 synthetic lethal genes may provide additional therapeutic benefits. Additionally, research progress on the functions of noncoding RNAs has made it clear that disrupting noncoding RNA networks has a favorable antitumor effect, supporting the hypothesis that targeting noncoding RNAs may have potential synthetic lethal effects in cancers with p53 mutations. The purpose of this review is to discuss treatments for cancers with mutant p53 that focus on directly targeting mutant p53, restoring wild-type functions, and exploiting synthetic lethal interactions with mutant p53. Additionally, the possibility of noncoding RNAs acting as synthetic lethal targets for mutant p53 will be discussed.

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Section: Synthetic Lethality With P53: a Strategy That Makes P53 Druggablementioning

confidence: 99%

Targeting mutant p53 for cancer therapy: direct and indirect strategies

et al. 2021

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“…With the massive effort of genomic studies and precision oncology approaches [15][16][17][18][19][20], it is well understood that millions of patients worldwide live with a p53 mutant expressing tumour, with subsequent potential defects in cell death [21][22][23][24] or autophagy [25][26][27][28][29], however this information does not currently reflect a benefit for patients as effective therapeutic approaches to target p53 gain-of-function (GOF) are still lacking. As p53 mutant proteins appear to be generally undruggable, deconvolution of the gene network mediating its oncogenic effect is proposed as a promising strategy to improve anti-cancer therapies and to complement the substantial effort of defining the wt p53 tumour suppressive network [30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

NUAK2 and RCan2 participate in the p53 mutant pro-tumorigenic network

et al. 2021

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Most inactivating mutations in TP53 gene generates neomorphic forms of p53 proteins that experimental evidence and clinical observations suggest to exert gain-of-function effects. While massive effort has been deployed in the dissection of wild type p53 transcriptional programme, p53 mutant pro-tumorigenic gene network is still largely elusive. To help dissecting the molecular basis of p53 mutant GOF, we performed an analysis of a fully annotated genomic and transcriptomic human pancreatic adenocarcinoma to select candidate players of p53 mutant network on the basis their differential expression between p53 mutant and p53 wild-type cohorts and their prognostic value. We identified NUAK2 and RCan2 whose p53 mutant GOF-dependent regulation was further validated in pancreatic cancer cellular model. Our data demonstrated that p53R270H can physically bind RCan2 gene locus in regulatory regions corresponding to the chromatin permissive areas where known binding partners of p53 mutant, such as p63 and Srebp, bind. Overall, starting from clinically relevant data and progressing into experimental validation, our work suggests NUAK2 and RCan2 as novel candidate players of the p53 mutant pro-tumorigenic network whose prognostic and therapeutic interest might attract future studies.

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“…Beyond the loss of gene copies, the mutation of TP53 often occurs in the DNA-binding domain (32). These TP53 mutations lead to decreased ability that transactivate downstream genes, and dysregulation of target genes accelerates NSCLC development (33,34). Although a number of lncRNAs were reported to be regulated by TP53 (35), whether TP53 modulates lncRNA GHRLOS in NSCLC is unknown.…”

Section: Introductionmentioning

confidence: 99%

TP53-Activated lncRNA GHRLOS Regulates Cell Proliferation, Invasion, and Apoptosis of Non-Small Cell Lung Cancer by Modulating the miR-346/APC Axis

et al. 2021

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Non-small cell lung cancer (NSCLC) is the main type of lung cancer with high mortality worldwide. To improve NSCLC therapy, the exploration of molecular mechanisms involved in NSCLC progression and identification of their potential therapy targeting is important. Long noncoding RNAs (lncRNAs) have shown important roles in regulating various tumors progression, including NSCLC. We found lncRNA GHRLOS was decreased in NSCLC cell lines and tissues which correlated with poor prognosis of NSCLC patients. However, the role and underlying mechanisms of lncRNA GHRLOS in NSCLC progression remains elusive. The expression of lncRNA GHRLOS was examined in NSCLC cell lines and biopsy specimens of patients with NSCLC by quantitative real time polymerase chain reaction (qRT-PCR). The effects of GHRLOS on proliferation, invasion and apoptosis of NSCLC cells were determined by both in vitro and in vivo experiments. The interaction between GHRLOS and TP53 was determined by dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) combined with qRT-PCR analysis. RNA immunoprecipitation (RIP) was conducted to validate the binding between GHRLOS and microRNA-346 (miR-346). Dual-luciferase reporter assays were also carried out to reveal the interaction between miR-346 and the 3’ untranslated region (3’UTR) of adenomatous polyposis coli (APC) mRNA.Our data demonstrated that overexpression of lncRNA GHRLOS suppressed cancer cell proliferation and invasion as well as promoted cell apoptosis by regulating the expression of CDK2, PCNA, E-cadherin, N-cadherin, Bax, and Bcl-2 in NSCLC cells. Moreover, lncRNA GHRLOS was upregulated by the binding of TP53 to the GHRLOS promoter. The binding target of lncRNA GHRLOS was identified to be miR-346. Impressively, overexpression of miR-346 promoted cell proliferation and invasion, as well as inhibited cell apoptosis, however, these effects can be blocked by overexpression of lncRNA GHRLOS both in vitro and in vivo. In summary, this study reveals lncRNA GHRLOS, upregulated by TP53, acts as a molecule sponge of miR-346 to cooperatively modulates expression of APC, a miR-346 target, and potentially inhibits NSCLC progression via TP53/lncRNA GHRLOS/miR-346/APC axis, which represents a novel pathway that could be useful in targeted therapy against NSCLC.

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Mutant p53 as a Regulator and Target of Autophagy

Cited by 39 publications

References 183 publications

Targeting mutant p53 for cancer therapy: direct and indirect strategies

Targeting mutant p53 for cancer therapy: direct and indirect strategies

NUAK2 and RCan2 participate in the p53 mutant pro-tumorigenic network

TP53-Activated lncRNA GHRLOS Regulates Cell Proliferation, Invasion, and Apoptosis of Non-Small Cell Lung Cancer by Modulating the miR-346/APC Axis

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