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

PLoS ONE ◽  
2014 ◽  
Vol 9 (8) ◽  
pp. e103497 ◽  
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

scholarly journals ErbB2 inhibition by lapatinib promotes degradation of mutant p53 protein in cancer cells

Oncotarget ◽  
2016 ◽  
Vol 8 (4) ◽  
pp. 5823-5833 ◽  
Author(s):  
Dun Li ◽  
Natalia D. Marchenko
Keyword(s):  
Cancer Cells ◽  
P53 Protein ◽  
Mutant P53

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

2017 ◽  
Vol 114 (29) ◽  
pp. 7623-7628 ◽  
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.

scholarly journals Targeting Therapies for the p53 Protein in Cancer Treatments

2019 ◽  
Vol 3 (1) ◽  
pp. 21-34 ◽  
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.

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

Cancers ◽  
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.

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

2018 ◽  
Vol 293 (12) ◽  
pp. 4262-4276 ◽  
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

scholarly journals Failure of wild-type p53 gene therapy in human cancer cells expressing a mutant p53 protein

Gene Therapy ◽  
1999 ◽  
Vol 6 (1) ◽  
pp. 22-33 ◽  
Author(s):  
A Vinyals ◽  
M A Peinado ◽  
M Gonzalez-Garrigues ◽  
M Monzó ◽  
R D Bonfil ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Cancer Cells ◽  
Human Cancer ◽  
P53 Protein ◽  
P53 Gene ◽  
Mutant P53 ◽  
Wild Type ◽  
Human Cancer Cells ◽  
Wild Type P53

scholarly journals Genome-wide CRISPR screens reveal APR-246 (Eprenetapopt) triggers ferroptosis and inhibits iron-sulfur cluster biogenesis

2020 ◽  
Author(s):  
Kenji M. Fujihara ◽  
Bonnie Zhang ◽  
Thomas D. Jackson ◽  
Brunda Nijiagel ◽  
Ching-Seng Ang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
De Novo ◽  
Clinical Investigation ◽  
P53 Protein ◽  
Covalent Modification ◽  
Mutant P53 ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Genome Wide

ABSTRACTThe mechanisms by which cells respond and adapt to oxidative stress are largely unknown but are key to developing a rationale for cancer therapies that target antioxidant pathways. APR-246 is a mutant-p53 targeted therapeutic currently under clinical investigation in myeloid dysplastic syndrome (MDS) and acute myeloid leukemia1. Whilst the mechanism of action of APR-246 is thought to be reactivation of wild-type p53 activity through covalent modification of cysteine residues in the core domain of mutant-p53 protein2,3, here we report that the anti-neoplastic capacity of APR-246 lies predominantly in the conjugation of free cysteine. Genome-wide CRISPR perturbation screening, metabolite profiling and proteomics in response to APR-246 treatment in mutant-p53 cancer cells highlighted the role of GSH and mitochondrial metabolism in determining APR-246 efficacy. APR-246 sensitivity was increased through loss of key enzymes in mitochondrial one-carbon metabolism, SHMT2 and MTHFD1L, due to diminished glycine supply for de novo GSH synthesis. Critically, we show that APR-246 induces iron-dependent, apoptotic machinery-independent cell death, ferroptosis. Whole-cell proteomics analyses indicated an upregulation of proteins involved in iron-sulfur cluster biogenesis (eg. FDX1). GSH, acetyl-CoA and NADH levels were also depleted in APR-246 treated cells. Importantly, we found that APR-246 inhibits iron-sulfur cluster biogenesis in the mitochondria of cancer cells through cysteine conjugation. This work not only details novel determinants of APR-246 activity in cancer cells, but also provides a clinical roadmap for targeting antioxidant pathways in tumours - beyond targeting mutant-p53 tumours.

Sign in / Sign up

Export Citation Format

Share Document