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• W2566564681 abstract "Tumor suppressor p53 is frequently mutated or inactivated in colorectal cancer while p53 family member p73 is rarely mutated in cancer cells. Small molecules that activate p73 can elicit a p53-like tumor suppressive function and represent a novel approach for p53 pathway restoration. Colorectal tumors contain a small population of cancer stem cells (CSCs) capable of self-renewal that contributes to tumor maintenance and resistance to therapy. Targeting CSCs could improve treatment response and prolong patient survival. We have previously shown that small molecule Prodigiosin restores the p53 pathway via activation of p73 and inhibition of the mutant p53-p73 interaction (Hong et al., Cancer Research 74:1153-1165, 2014). We now demonstrate that prodigiosin targets 5-Fluorouracil-resistant CSCs along with bulk tumor cells. Prodigiosin prevents colonosphere formation of CRC cell lines independent of p53 status of the cells. Prodigiosin reduces the viability of both CSCs and non-CSCs while 5-Fluorouracil only targets non-CSCs. Prodigiosin significantly reduces the growth of xenograft tumors initiated in mice with CSCs without toxic effects and prevents the passage of these tumors. In a p53-reponsive luciferase reporter assay, prodigiosin induces p53-pathway transcription in colonospheres and CSC-initiated xenograft tumors. Stable shRNA knockdown of p73 revealed that prodigiosin inhibits the self-renewal of CSCs in a p73-dependent manner. Next, we explored the mechanisms of prodigiosin-mediated p53-pathway restoration and anti-CSC effects upstream of p73 activation. The oncogenic N-terminally truncated isoform ΔNp73 is a dominant negative inhibitor of p73 and p53. ΔNp73 levels correlate with poor overall survival in colorectal cancer patients. Western blot analysis revealed that prodigiosin increases protein levels of p73 and its target genes and reduces levels of the oncogenic isoform ΔNp73. Prodigiosin has been previously shown to increase the expression of c-Jun, a member of the AP-1 family of transcription factors. c-Jun is known to regulate the induction of p73 and degradation of ΔNp73 in response to cellular stress. We hypothesized that prodigiosin mediated p53-pathway restoration involves c-Jun upregulation resulting in ΔNp73 inhibition and p73 activation. Western blot analysis revealed that prodigiosin induces levels of c-Jun and phospho-c-Jun. siRNA knockdown of c-Jun protein levels reduced prodigiosin-mediated ΔNp73 downregulation. Thus, we have characterized a previously unrecognized mechanism of prodigiosin-mediated p73 activation via c-Jun-dependent ΔNp73 inhibition. Ongoing experiments involve further validation of the mechanism by studying the effects of c-Jun knockdown and ΔNp73 overexpression on Prodigiosin-mediated effects on apoptosis, CSC self-renewal and p53 pathway restoration. Citation Format: Varun Vijay Prabhu, Shengliang Zhang, Bo Hong, Joshua E. Allen, Amriti Lulla, David T. Dicker, Wafik S. El-Deiry. Small molecule Prodigiosin-mediated p53 pathway restoration and inhibition of self-renewal in colorectal cancer involves c-Jun-mediated ΔNp73 inhibition and p73 activation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1215. doi:10.1158/1538-7445.AM2015-1215" @default.
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• W2566564681 date "2015-08-01" @default.
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• W2566564681 title "Abstract 1215: Small molecule Prodigiosin-mediated p53 pathway restoration and inhibition of self-renewal in colorectal cancer involves c-Jun-mediated ΔNp73 inhibition and p73 activation" @default.
• W2566564681 doi "https://doi.org/10.1158/1538-7445.am2015-1215" @default.
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