p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms

Pitolli, Consuelo; Wang, Ying; Candi, Eleonora; Shi, Yufang; Melino, Gerry; Amelio, Ivano

doi:10.3390/cancers11121983

Cited by 64 publications

(50 citation statements)

References 100 publications

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“…Originally identified as a major executor of the response to DNA damage, with a more recent revision, p53 is considered a molecular hub for the interactions between stressors (reactive oxygen radicals [ROS], nutrient deprivation, hypoxia, telomere erosion, etc.) and cellular biological responses [5][6][7][8][9][10][11][12] (Fig. 1).…”

Section: Questionsmentioning

confidence: 99%

Context is everything: extrinsic signalling and gain-of-function p53 mutants

Amelio

Melino

2020

Cell Death Discov.

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The TP53 genomic locus is a target of mutational events in at least half of cancers. Despite several decades of study, a full consensus on the relevance of the acquisition of p53 gain-of-function missense mutants has not been reached. Depending on cancer type, type of mutations and other unidentified factors, the relevance for tumour development and progression of the oncogenic signalling directed by p53 mutants might significantly vary, leading to inconsistent observations that have fuelled a long and fierce debate in the field. Here, we discuss how interaction with the microenvironment and stressors might dictate the gain-of-function effects exerted by individual mutants. We report evidence from the most recent literature in support of the context dependency of p53 mutant biology. This perspective article aims to raise a discussion in the field on the relevance that context might have on p53 gain-offunction mutants, assessing whether this should generally be considered a cell non-autonomous process. Facts • Mutant p53 GOF effects have been shown to vary in different settings, potentially depending on cancer types, experimental models and conditions. • Reciprocal interaction between microenvironment and mutant p53 GOF effects exists.

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Section: Questionsmentioning

confidence: 99%

Context is everything: extrinsic signalling and gain-of-function p53 mutants

Amelio

Melino

2020

Cell Death Discov.

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“…ROS can function as both an upstream signal that activates p53 and as a downstream factor that facilitates apoptosis [ 53 ]. In non-stressed cells, proteasomal degradation by mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin ligases and MDM4 can help maintain low levels of p53 [ 55 ]. However, in stressed cells such as cells having ROS mediated DNA damage, p53 is stabilized and activated by post-translational modifications, including multi-site phosphorylation, acetylation, and methylation [ 53 ].…”

Section: P53: a Key Mediator Of Ros-induced Apoptosismentioning

confidence: 99%

Pro-oxidant Actions of Carotenoids in Triggering Apoptosis of Cancer Cells: A Review of Emerging Evidence

et al. 2020

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Carotenoids are well known for their potent antioxidant function in the cellular system. However, in cancer cells with an innately high level of intracellular reactive oxygen species (ROS), carotenoids may act as potent pro-oxidant molecules and trigger ROS-mediated apoptosis. In recent years, the pro-oxidant function of several common dietary carotenoids, including astaxanthin, β-carotene, fucoxanthin, and lycopene, has been investigated for their effective killing effects on various cancer cell lines. Besides, when carotenoids are delivered with ROS-inducing cytotoxic drugs (e.g., anthracyclines), they can minimize the adverse effects of these drugs on normal cells by acting as antioxidants without interfering with their cytotoxic effects on cancer cells as pro-oxidants. These dynamic actions of carotenoids can optimize oxidative stress in normal cells while enhancing oxidative stress in cancer cells. This review discusses possible mechanisms of carotenoid-triggered ROS production in cancer cells, the activation of pro-apoptotic signaling by ROS, and apoptotic cell death. Moreover, synergistic actions of carotenoids with ROS-inducing anti-cancer drugs are discussed, and research gaps are suggested.

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“…107 The main regulator of p53 is a ubiquitin ligase, mouse double minute 2 (MDM2), which results in proteasome ubiquitination of the tumor suppressor. 108 As mentioned earlier, Ras signaling is also essential in inactivation of p53mediated induction of p21Cip1. 100 Therapeutic targets within this pathway are needed since TP53 is mutated in over 50% of cancers and in mCRPC, an aberration causing loss of function is found in 36-53% of patients (Table 1).…”

Section: Tp53 Axismentioning

confidence: 83%

<p>Novel Therapeutic Strategies for CDK4/6 Inhibitors in Metastatic Castrate-Resistant Prostate Cancer</p>

Kase¹,

Copland²,

Tan³

2020

OTT

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The majority of patients with castrate-resistant prostate cancer will have metastatic disease at the time of diagnosis. Investigative efforts on new therapeutics for this patient population have improved with the development of androgen signaling inhibitors, such as abiraterone and enzalutamide, and PARP inhibitors, such as rucaparib and olaparib, to accompany the previously FDA-approved docetaxel, cabazitaxel, sipuleucel-T, and Radium 223. However, new therapeutic strategies are necessary to prolong survival as progression after these agents is inevitable. CDK4/6 inhibitors have advanced the field of estrogen receptor positive breast cancer treatment and are being investigated in prostate cancer given the role of androgen receptor signaling effects on the cell cycle. Response to CDK4/6 inhibitors may be predicted by the tumors' genomic profile and may provide insight into combinatory therapy with CDK4/6 inhibitors in order to delay resistance or provide synergistic effects. Here, we review the use of CDK4/6 inhibitors in prostate cancer and potential combinations based on known resistance mechanisms to CDK4/6 inhibitors, prostate cancer regulatory pathways, and prostate-cancer-specific genomic alterations.

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p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms

Cited by 64 publications

References 100 publications

Context is everything: extrinsic signalling and gain-of-function p53 mutants

Context is everything: extrinsic signalling and gain-of-function p53 mutants

Pro-oxidant Actions of Carotenoids in Triggering Apoptosis of Cancer Cells: A Review of Emerging Evidence

<p>Novel Therapeutic Strategies for CDK4/6 Inhibitors in Metastatic Castrate-Resistant Prostate Cancer</p>

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