MDM2 and MDMX are the primary negative regulators of p53, which under normal conditions maintain low intracellular levels of p53 by targeting it to the proteasome for rapid degradation and inhibiting ...its transcriptional activity. Both MDM2 and MDMX function as powerful oncogenes and are commonly over-expressed in some cancers, including sarcoma (~20%) and breast cancer (~15%). In contrast to tumors that are p53 mutant, whereby the current therapeutic strategy restores the normal active conformation of p53, MDM2 and MDMX represent logical therapeutic targets in cancer for increasing wild-type (WT) p53 expression and activities. Recent preclinical studies suggest that there may also be situations that MDM2/X inhibitors could be used in p53 mutant tumors. Since the discovery of nutlin-3a, the first in a class of small molecule MDM2 inhibitors that binds to the hydrophobic cleft in the N-terminus of MDM2, preventing its association with p53, there is now an extensive list of related compounds. In addition, a new class of stapled peptides that can target both MDM2 and MDMX have also been developed. Importantly, preclinical modeling, which has demonstrated effective in vitro and in vivo killing of WT p53 cancer cells, has now been translated into early clinical trials allowing better assessment of their biological effects and toxicities in patients. In this overview, we will review the current MDM2- and MDMX-targeted therapies in development, focusing particularly on compounds that have entered into early phase clinical trials. We will highlight the challenges pertaining to predictive biomarkers for and toxicities associated with these compounds, as well as identify potential combinatorial strategies to enhance its anti-cancer efficacy.
Awareness of the importance of immunity in controlling cancer development triggered research into the impact of its key oncogenic drivers on the immune response, as well as their value as targets for ...immunotherapy. At the heart of tumour suppression is p53, which was discovered in the context of viral infection and now emerges as a significant player in normal and cancer immunity. Wild-type p53 (wt p53) plays fundamental roles in cancer immunity and inflammation. Mutations in p53 not only cripple wt p53 immune functions but also sinisterly subvert the immune function through its neomorphic gain-of-functions (GOFs). The prevalence of mutant p53 across different types of human cancers, which are associated with inflammatory and immune dysfunction, further implicates mutant p53 in modulating cancer immunity, thereby promoting tumorigenesis, metastasis and invasion. In this review, we discuss several mutant p53 immune GOFs in the context of the established roles of wt p53 in regulating and responding to tumour-associated inflammation, and regulating innate and adaptive immunity. We discuss the capacity of mutant p53 to alter the tumour milieu to support immune dysfunction, modulate toll-like receptor (TLR) signalling pathways to disrupt innate immunity and subvert cell-mediated immunity in favour of immune privilege and survival. Furthermore, we expose the potential and challenges associated with mutant p53 as a cancer immunotherapy target and underscore existing therapies that may benefit from inquiry into cancer p53 status.
There are many differences in cancer manifestation between men and women. New understanding of the origin of these point to fundamental distinctions in the genetic code and its demise. Tumour ...suppressor protein p53 is the chief operating officer of cancer defence and critically acts to safeguard against sustained DNA damaged. P53 cannot be ignored in cancer sex disparity. In this review we discuss the greater prevalence and associated death rates for non-reproductive cancers in males. The major tumour suppressor protein p53, encoded in the
gene is our chosen context. It is fitting to ask why somatic
mutation incidence is estimated to be disproportionately higher among males in the population for these types of cancers compared with females? We scrutinised the literature for evidence of predisposing genetic and epigenetic alterations that may explain this sex bias. Our second approach was to explore whether redox activity, either externally imposed or inherent to males and females, may define distinct risks that could contribute to the clear cancer sex disparities.
Cellular senescence is characterised by the irreversible arrest of proliferation, a pro-inflammatory secretory phenotype and evasion of programmed cell death mechanisms. We report that senescence ...alters cellular iron acquisition and storage and also impedes iron-mediated cell death pathways. Senescent cells, regardless of stimuli (irradiation, replicative or oncogenic), accumulate vast amounts of intracellular iron (up to 30-fold) with concomitant changes in the levels of iron homeostasis proteins. For instance, ferritin (iron storage) levels provided a robust biomarker of cellular senescence, for associated iron accumulation and for resistance to iron-induced toxicity. Cellular senescence preceded iron accumulation and was not perturbed by sustained iron chelation (deferiprone). Iron accumulation in senescent cells was driven by impaired ferritinophagy, a lysosomal process that promotes ferritin degradation and ferroptosis. Lysosomal dysfunction in senescent cells was confirmed through several markers, including the build-up of microtubule-associated protein light chain 3 (LC3-II) in autophagosomes. Impaired ferritin degradation explains the iron accumulation phenotype of senescent cells, whereby iron is effectively trapped in ferritin creating a perceived cellular deficiency. Accordingly, senescent cells were highly resistant to ferroptosis. Promoting ferritin degradation by using the autophagy activator rapamycin averted the iron accumulation phenotype of senescent cells, preventing the increase of TfR1, ferritin and intracellular iron, but failed to re-sensitize these cells to ferroptosis. Finally, the enrichment of senescent cells in mouse ageing hepatic tissue was found to accompany iron accumulation, an elevation in ferritin and mirrored our observations using cultured senescent cells.
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•Altered iron homeostasis in senescent cells is driven by impaired ferritinophagy.•Impaired ferritinophagy causes functional cellular iron deficiency.•senescent cells are resistant to iron mediated cell death including ferroptosis.
Abstract
TP53
, a critical tumour suppressor gene, is mutated in over half of all cancers resulting in mutant-p53 protein accumulation and poor patient survival. Therapeutic strategies to target ...mutant-p53 cancers are urgently needed. We show that accumulated mutant-p53 protein suppresses the expression of
SLC7A11
, a component of the cystine/glutamate antiporter, system x
C
−
, through binding to the master antioxidant transcription factor NRF2. This diminishes glutathione synthesis, rendering mutant-p53 tumours susceptible to oxidative damage. System x
C
−
inhibitors specifically exploit this vulnerability to preferentially kill cancer cells with stabilized mutant-p53 protein. Moreover, we demonstrate that
SLC7A11
expression is a novel and robust predictive biomarker for APR-246, a first-in-class mutant-p53 reactivator that also binds and depletes glutathione in tumours, triggering lipid peroxidative cell death. Importantly, system x
C
−
antagonism strongly synergizes with APR-246 to induce apoptosis in mutant-p53 tumours. We propose a new paradigm for targeting cancers that accumulate mutant-p53 protein by inhibiting the SLC7A11–glutathione axis.
Exposure to cellular stress can trigger the p53 tumor suppressor, a sequence-specific transcription factor, to induce cell growth arrest or apoptosis. The choice between these cellular responses is ...influenced by many factors, including the type of cell and stress, and the action of p53 co-activators. p53 stimulates a wide network of signals that act through two major apoptotic pathways. The extrinsic, death receptor pathway triggers the activation of a caspase cascade, and the intrinsic, mitochondrial pathway shifts the balance in the Bcl-2 family towards the pro-apoptotic members, promoting the formation of the apoptosome, and consequently caspase-mediated apoptosis. The impact of these two apoptotic pathways may be enhanced when they converge through Bid, which is a p53 target. The majority of these apoptotic effects are mediated through the induction of specific apoptotic target genes. However, p53 can also promote apoptosis by a transcription-independent mechanism under certain conditions. Thus, a multitude of mechanisms are employed by p53 to ensure efficient induction of apoptosis in a stage-, tissue- and stress-signal-specific manner. Manipulation of the apoptotic functions of p53 constitutes an attractive target for cancer therapy.
Crucial, natural protection against tumour onset in humans is orchestrated by the dynamic protein p53. The best-characterised functions of p53 relate to its cellular stress responses. In this review, ...we explore emerging insights into p53 activities and their functional consequences. We compare p53 in humans and elephants, in search of salient features of cancer protection.
The disproportionately high prevalence of male cancer is poorly understood. We tested for sex-disparity in the functional integrity of the major tumor suppressor p53 in sporadic cancers. Our ...bioinformatics analyses expose three novel levels of p53 impact on sex-disparity in 12 non-reproductive cancer types. First, TP53 mutation is more frequent in these cancers among US males than females, with poorest survival correlating with its mutation. Second, numerous X-linked genes are associated with p53, including vital genomic regulators. Males are at unique risk from alterations of their single copies of these genes. High expression of X-linked negative regulators of p53 in wild-type TP53 cancers corresponds with reduced survival. Third, females exhibit an exceptional incidence of non-expressed mutations among p53-associated X-linked genes. Our data indicate that poor survival in males is contributed by high frequencies of TP53 mutations and an inability to shield against deregulated X-linked genes that engage in p53 networks.
The tumor suppressor p53 normally acts as a brake to halt damaged cells from perpetrating their genetic errors into future generations. If p53 is disrupted by mutation, it may not only lose these ...corrective powers, but counterproductively acquire new capacities that drive cancer. A newly emerging manner in which mutant p53 executes its cancer promoting functions is by harnessing key proteins, which normally partner with its wild type, tumor-inhibiting counterpart. In association with the subverted activities of these protein partners, mutant p53 is empowered to act across multiple fundamental cellular pathways (regulating cell division and metabolism) and corrupt them to become cancer promoting.
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