Abstract 3694: Selective killing of cancer cells by the styryl lactone (R)- goniothalamin is mediated through glutathione conjugation, oxidative stress and a marked reactivation of the R175H mutant p53 protein

The compound APR-246 (PRIMA-1MET) is a known reactivator of (mutant) p53 and inducer of oxidative stress which can sensitize cancer cells to platinum-based chemotherapeutics. However, the effect of a hypoxic tumor environment has been largely overlooked in this interaction. This study focusses on the role of hypoxia-inducible factor-1α (HIF-1α) and the p53 tumor suppressor protein in hypoxia-induced cisplatin resistance in non-small cell lung cancer (NSCLC) cells and the potential of APR-246 to overcome this resistance. We observed that hypoxia-induced cisplatin resistance only occurred in the p53 mutant NCI-H2228Q331* cell line, and not in the wild type A549 and mutant NCI-H1975R273H cell lines. Cisplatin reduced HIF-1α protein levels in NCI-H2228Q331* cells, leading to a shift in expression from HIF-1α-dependent to p53-dependent transcription targets under hypoxia. APR-246 was able to overcome hypoxia-induced cisplatin resistance in NCI-H2228Q331* cells in a synergistic manner without affecting mutant p53Q331* transcriptional activity, but significantly depleting total glutathione levels more efficiently under hypoxic conditions. Synergism was dependent on the presence of mutant p53Q331* and the induction of reactive oxygen species, with depletion of one or the other leading to loss of synergism. Our data further support the rationale of combining APR-246 with cisplatin in NSCLC, since their synergistic interaction is retained or enforced under hypoxic conditions in the presence of mutant p53.

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Mutant p53 potentiates the oncogenic effects of insulin by inhibiting the tumor suppressor DAB2IP

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1700996114 ◽

2017 ◽

Vol 114 (29) ◽

pp. 7623-7628 ◽

Cited By ~ 12

Author(s):

Elena Valentino ◽

Arianna Bellazzo ◽

Giulio Di Minin ◽

Daria Sicari ◽

Mattia Apollonio ◽

...

Keyword(s):

Tumor Suppressor ◽

Cancer Cells ◽

P53 Protein ◽

Significant Risk ◽

Protein S ◽

Mutant P53 ◽

Cancer Evolution ◽

Insulin Stimulation ◽

Interacting Protein ◽

Frequent Event

Obesity and type 2 diabetes are significant risk factors for malignancies, being associated with chronic inflammation and hyperinsulinemia. In this context, insulin can synergize with inflammation to promote proliferation, survival, and dissemination of cancer cells. Point mutation of p53 is a frequent event and a significant factor in cancer development and progression. Mutant p53 protein(s) (mutp53) can acquire oncogenic properties that increase metastasis, proliferation, and cell survival. We report that breast and prostate cancer cells with mutant p53 respond to insulin stimulation by increasing cell proliferation and invasivity, and that such a response depends on the presence of mutp53. Mechanistically, we find that mutp53 augments insulin-induced AKT1 activation by binding and inhibiting the tumor suppressor DAB2IP (DAB2-interacting protein) in the cytoplasm. This molecular axis reveals a specific gain of function for mutant p53 in the response to insulin stimulation, offering an additional perspective to understand the relationship between hyperinsulinemia and cancer evolution.

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Arsenic Trioxide Reactivates Proteasome-Dependent Degradation of Mutant p53 Protein in Cancer Cells in Part via Enhanced Expression of Pirh2 E3 Ligase

PLoS ONE ◽

10.1371/journal.pone.0103497 ◽

2014 ◽

Vol 9 (8) ◽

pp. e103497 ◽

Cited By ~ 19

Author(s):

Wensheng Yan ◽

Yong-Sam Jung ◽

Yanhong Zhang ◽

Xinbin Chen

Keyword(s):

Cancer Cells ◽

Arsenic Trioxide ◽

P53 Protein ◽

E3 Ligase ◽

Mutant P53 ◽

Enhanced Expression

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Targeting Therapies for the p53 Protein in Cancer Treatments

Annual Review of Cancer Biology ◽

10.1146/annurev-cancerbio-030518-055455 ◽

2019 ◽

Vol 3 (1) ◽

pp. 21-34 ◽

Cited By ~ 20

Author(s):

Arnold J. Levine

Keyword(s):

Cancer Cells ◽

P53 Protein ◽

Mutant P53 ◽

Loss Of Function ◽

Protein Antigens ◽

Protein Loss ◽

Cancer Treatments ◽

Synthetic Lethal ◽

Gene Therapies ◽

Cellular Immune

Half of all human cancers contain TP53 mutations, and in many other cancers, the function of the p53 protein is compromised. The diversity of these mutations and phenotypes presents a challenge to the development of drugs that target p53 mutant cancer cells. This review describes the rationale for many different approaches in the development of p53 targeted therapies: ( a) viruses and gene therapies, ( b) increased levels and activity of wild-type p53 proteins in cancer cells, ( c) p53 protein gain-of-function inhibitors, ( d) p53 protein loss-of-function structural correctors, ( e) mutant p53 protein synthetic lethal drugs interfering with the p53 pathway, and ( f) cellular immune responses to mutant p53 protein antigens. As these types of therapies are developed, tested, and evaluated, the best of them will have a significant impact upon cancer treatments and possibly prevention.

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Cancer Cells Shuttle Extracellular Vesicles Containing Oncogenic Mutant p53 Proteins to the Tumor Microenvironment

Cancers ◽

10.3390/cancers13122985 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2985

Author(s):

Bibek Bhatta ◽

Ishai Luz ◽

Christian Krueger ◽

Fanny Xueting Teo ◽

David P. Lane ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Extracellular Vesicles ◽

P53 Protein ◽

Mutant P53 ◽

P53 Expression ◽

Carcinoma Cell Lines ◽

Cancer Types ◽

Molecular Information ◽

Shed Light

Extracellular vesicles (EVs) shed by cancer cells play a major role in mediating the transfer of molecular information by reprogramming the tumor microenvironment (TME). TP53 (encoding the p53 protein) is the most mutated gene across many cancer types. Mutations in TP53 not only result in the loss of its tumor-suppressive properties but also results in the acquisition of novel gain-of-functions (GOF) that promote the growth of cancer cells. Here, we demonstrate that GOF mutant p53 proteins can be transferred via EVs to neighboring cancer cells and to macrophages, thus modulating them to release tumor supportive cytokines. Our data from pancreatic, lung, and colon carcinoma cell lines demonstrate that the mutant p53 protein can be selectively sorted into EVs. More specifically, mutant p53 proteins in EVs can be taken up by neighboring cells and mutant p53 expression is found in non-tumor cells in both human cancers and in non-human tissues in human xenografts. Our findings shed light on the intricate methods in which specific GOF p53 mutants can promote oncogenic mechanisms by reprogramming and then recruiting non-cancerous elements for tumor progression.

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The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53

Journal of Biological Chemistry ◽

10.1074/jbc.ra117.000950 ◽

2018 ◽

Vol 293 (12) ◽

pp. 4262-4276 ◽

Cited By ~ 17

Author(s):

Esha Madan ◽

Taylor M. Parker ◽

Matthias R. Bauer ◽

Alisha Dhiman ◽

Christopher J. Pelham ◽

...

Keyword(s):

Cancer Cells ◽

P53 Protein ◽

Mutant P53 ◽

Curcumin Analog

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Transketolase regulates sensitivity to APR-246 in p53-null cells independently of oxidative stress modulation

Scientific Reports ◽

10.1038/s41598-021-83979-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Julia V. Milne ◽

Bonnie Z. Zhang ◽

Kenji M. Fujihara ◽

Swati Dawar ◽

Wayne A. Phillips ◽

...

Keyword(s):

Oxidative Stress ◽

Targeted Therapy ◽

P53 Protein ◽

Pentose Phosphate ◽

Antioxidant Systems ◽

Mutant P53 ◽

Complex Mechanism ◽

Increased Sensitivity ◽

The Relationship ◽

Tumour Suppressor P53

AbstractThe prevalence and dire implications of mutations in the tumour suppressor, p53, highlight its appeal as a chemotherapeutic target. We recently showed that impairing cellular antioxidant systems via inhibition of SLC7A11, a component of the system xc− cystine-glutamate antiporter, enhances sensitivity to mutant-p53 targeted therapy, APR-246. We investigated whether this synergy extends to other genes, such as those encoding enzymes of the pentose phosphate pathway (PPP). TKT, one of the major enzymes of the PPP, is allegedly regulated by NRF2, which is in turn impaired by accumulated mutant-p53 protein. Therefore, we investigated the relationship between mutant-p53, TKT and sensitivity to APR-246. We found that mutant-p53 does not alter expression of TKT, nor is TKT modulated directly by NRF2, suggesting a more complex mechanism at play. Furthermore, we found that in p53null cells, knockdown of TKT increased sensitivity to APR-246, whilst TKT overexpression conferred resistance to the drug. However, neither permutation elicited any effect on cells overexpressing mutant-p53 protein, despite mediating oxidative stress levels in a similar fashion to that in p53-null cells. In sum, this study has unveiled TKT expression as a determinant for sensitivity to APR-246 in p53-null cells.

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