Targeting Tumor Suppressor p53 for Cancer Therapy: Strategies, Challenges and Opportunities

Hong, Bo; Heuvel, A. Pieter J. van den; Prabhu, Varun V.; Zhang, Shengliang; El‐Deiry, Wafik S.

doi:10.2174/1389450114666140106101412

Cited by 221 publications

(150 citation statements)

References 97 publications

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“…There are several strategies to target p53, including inhibition of p53 degradation through disrupting the p53-HDM2 interaction, gene therapy that introduces wild-type p53 into cancers, restoration of mutant p53 to wild-type p53, elimination of mutant p53, and p53-based vaccines (reviewed in ref. 57). The conventional strategies for restoration of p53 function in tumors are aimed at protecting wild-type p53 from proteasomal degradation.…”

Section: Implications For Interactions Among P53 Estrogen and Er Inmentioning

confidence: 99%

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

2015

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The tumor suppressor p53 has established functions in cancer. Specifically, it has been shown to cause cell-cycle arrest and apoptosis in response to DNA damage. It is also one of the most commonly mutated or silenced genes in cancer and for this reason has been extensively studied. Recently, the role of p53 has been shown to go beyond its effects on cell cycle and apoptosis, with effects on metabolism emerging as a key contributor to cancer growth in situations where p53 is lost. Beyond this, the role of p53 in the tumor microenvironment is poorly understood. The publication by Wang and colleagues demonstrates for the first time that p53 is a key negative regulator of aromatase and, hence, estrogen production in the breast tumor microenvironment. It goes further by demonstrating that an important regulator of aromatase, the obesity-associated and tumor-derived factor prostaglandin E 2 , inhibits p53 in the breast adipose stroma. This review presents these findings in the context of established and emerging roles of p53 and discusses possible implications for the treatment of breast cancer. Cancer Res; 75(23); 5001-7. Ó2015 AACR.

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Section: Implications For Interactions Among P53 Estrogen and Er Inmentioning

confidence: 99%

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

2015

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“…TP53 and ARID1A are among potential sarcomatoid-specific targets for which therapeutics are in development (58,59). As drugs that mitigate effects of mutation in these genes enter clinical trials, their study in sarcomatoid renal tumors may be warranted.…”

Section: Discussionmentioning

confidence: 99%

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.

Bi¹

2016

JCO

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The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs,), increased frequency of nonsynonymous SSNVs in PanCancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10 −17 ); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers ATrich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.

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“…The cytoplasmic interaction of p53 with the anti-apoptotic Bcl-2 family proteins in the mitochondria induces the release of apoptogenic factors such as cytochrome c from the mitochondrial outer membrane. In addition, p53 can interact directly with Bak and/or Bax and activate these through a "hit and run" mechanism that prompts the permeabilization of the outer mitochondrial membrane targeting p53 family proteins, inhibition of p53-MDM2 interaction, restoring mutated p53 back to their wild-type functions, eliminating mutant p53, creating p53-based vaccines, and gene therapy to restore p53 function (Table 1) (Hong et al, 2014). The function of p53 is negatively regulated by oncoproteins such as MDM2 (known as HDM2 in humans) and MDMX through an interaction with the p53 transactivation domain (p53TAD) (Oliner et al, 1993).…”

Section: Targeting P53mentioning

confidence: 99%

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

Goldar¹,

Khaniani²,

Derakhshan³

et al. 2015

Asian Pacific Journal of Cancer Prevention

500

338

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Programmed cell death (PCD) or apoptosis is a mechanism which is crucial for all multicellular organisms to control cell proliferation and maintain tissue homeostasis as well as eliminate harmful or unnecessary cells from an organism. Defects in the physiological mechanisms of apoptosis may contribute to different human diseases like cancer. Identification of the mechanisms of apoptosis and its effector proteins as well as the genes responsible for apoptosis has provided a new opportunity to discover and develop novel agents that can increase the sensitivity of cancer cells to undergo apoptosis or reset their apoptotic threshold. These novel targeted therapies include those targeting anti-apoptotic Bcl-2 family members, p53, the extrinsic pathway, FLICE-inhibitory protein (c-FLIP), inhibitor of apoptosis (IAP) proteins, and the caspases. In recent years a number of these novel agents have been assessed in preclinical and clinical trials. In this review, we introduce some of the key regulatory molecules that control the apoptotic pathways, extrinsic and intrinsic death receptors, discuss how defects in apoptotic pathways contribute to cancer, and list several agents being developed to target apoptosis.

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Targeting Tumor Suppressor p53 for Cancer Therapy: Strategies, Challenges and Opportunities

Cited by 221 publications

References 97 publications

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

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