Small-Molecule Prodigiosin Restores p53 Tumor Suppressor Activity in Chemoresistant Colorectal Cancer Stem Cells via c-Jun-Mediated delta-Np73 Inhibition and p73 Activation

Author: Prabhu, Varun V.; Hong, Bo; Allen, Joshua E.; Zhang, Shengliang; Lulla, Amriti R.; Dicker, David T.; El-Deiry, Wafik S.

Description: Tumor suppressor p53 is frequently mutated or inactivated in colorectal cancer. In contrast, p53 family member p73 is rarely mutated in colorectal cancer and p73 activation elicits p53-like tumor suppression. Colorectal cancer stem cells (CRCSC) comprise a rare self-renewing subpopulation that contributes to tumor maintenance and chemoresistance. p53 restoration is known to target CRCSCs, but p73 restoration in CRCSCs has not been examined. In this study, we investigated the effects of the small-molecule prodigiosin, which restores the p53 pathway in tumor cells via p73 activation, on CRCSCs in vitro and in vivo Prodigiosin prevented colonosphere formation independent of p53 status and reduced the viability of self-renewing, 5-fluorouracil-resistant Aldefluor positive [Aldefluor(+)] CRCSCs in vitro.  Furthermore, prodigiosin inhibited the growth of xenograft tumors initiated with Aldefluor+ cells without toxic effects and limited the tumorigenic potential of these cells. Consistently, prodigiosin induced activation of a p53-responsive luciferase reporter in colonospheres, Aldefluor(+) cells, and tumor xenografts. Mechanistic studies revealed that prodigiosin increased the levels of p73 and reduced levels of the oncogenic N-terminally truncated isoform delta-Np73 in Aldefluor(+) cells. Accordingly, p73 knockdown or delta-Np73 overexpression suppressed prodigiosin-mediated inhibition of colonosphere formation. Moreover, prodigiosin increased levels of the transcription factor c-Jun, a regulator of p73 and delta-Np73, in both the cytoplasm and nucleus. c-Jun knockdown attenuated prodigiosin-mediated p53-reporter activation, delta-Np73 downregulation, p73 activation, and cell death. Collectively, our findings highlight the previously uncharacterized use of p73-activating therapeutics to target CRCSCs.

Subject headings: Animals; Anti-Bacterial Agents; Colorectal Neoplasms; Humans; Mice; Neoplastic Stem Cells; Nuclear Proteins; Prodigiosin; Signal Transduction; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays; Colorectal Cancer

Publication year: 2016

Journal or book title: Cancer Research

Volume: 76

Issue: 7

Pages: 1989-1999

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Serial number: 3695

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