Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53

Abstract

The tumor suppressor p53 prevents cancer development via initiating cell cycle arrest, cell death, repair, or anti-angiogenesis processes. Over 50% of human cancers harbor cancer-causing mutant p53. p53 mutations not only abrogate its tumor suppressor function, but also endow mutant p53 with a gain-of-function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression and chemo- or radiotherapy resistance. Thus, targeting mutant p53 to restore a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We demonstrate that small molecule NSC59984 not only restores wild-type p53 signaling, but also depletes mutant p53 GOF. NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin-proteasome pathway. NSC59984 restores wild-type p53 signaling via p73 activation specifically in mutant p53-expressing colorectal cancer cells. At therapeutic doses, NSC59984 induces p73-dependent cell death in cancer cells with minimal genotoxicity and without evident toxicity towards normal cells. NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73-dependent manner in vivo. We hypothesize that specific targeting of mutant p53 may be essential for anti-cancer strategies that involve the stimulation of p73 in order to efficiently restore tumor suppression. Taken together, our data identify NSC59984 as a promising lead compound for anti-cancer therapy that acts by targeting GOF mutant p53 and stimulates p73 to restore the p53 pathway signaling.

Crude Extracts, Flavokawain B and Alpinetin Compounds from the Rhizome of Alpinia mutica Induce Cell Death via UCK2 Enzyme Inhibition and in Turn Reduce 18S rRNA Biosynthesis in HT-29 Cells

“…Similarly, p53 stabilisation have also been demonstrated in cancer cells expressing R273H mutant p53 such as HT-29 following treatment with various agents. The induction of cell death of cancer expressing R273H mutant p53 is either by restoring the wild-type p53 activity leading to its stabilisation [35–42] or by restoring sequence-specific DNA binding of mutant p53 [43,44], or by depleting mutant p53 with minimal effect on the wild-type p53 [45–51]. In the present study, the ability of the bioactive compounds of FKB and APN to specifically influence the disruption of MDM2-p53 complex, thereby causing direct activation of p53, which is essential in triggering cell cycle arrest and apoptosis in HT-29 cells was demonstrated.…”

ZEB1-induced tumourigenesis requires senescence inhibition via activation of DKK1/mutant p53/Mdm2/CtBP and repression of macroH2A1

“…Our results in SW480 cells indicate that ZEB1, through DKK1, activates mutant TP53 and that ZEB1 is also under positive regulation by TP53 , indicating the existence of a positive feedback loop between both transcription factors. Of note, EMT-activating and ZEB1-activating mutations of TP53 (at least, R175H and R273H) are common in primary CRCs and CRC cell lines, including those used in this study 42 46. Wild-type and mutant p53 vary in their target genes and also in their transcriptional activities for a given gene with some genes being regulated in different directions (eg, activation vs repression) and others to different degree (eg, deficient or enhanced activation) 43…”

Protein regulator of cytokinesis-1 expression: prognostic value in lung squamous cell carcinoma patients

“…We then found overexpression of PRC1 protein associated with metastasis of lymph node and was an independent poor prognostic marker for lung SCC patients. There is sufficient evidence that p53 enhances the sensitivity of tumor cells to chemotherapy and radiotherapy, induces cell cycle arrest and inhibits cell growth and the proliferation of tumor cells (21)(22)(23). Li et al (24) showed that p53 directly suppresses PRC1 gene transcription.…”