Abstract 3908: miR-3132 induces TRAIL and cell death in mutant p53-expressing cancer cells

Abstract

Abstract Tumor suppressor p53, guardian of the genome, is frequently mutated or functionally dysregulated in more than 50% of human tumors. p53 mutation is a later event in tumorigenesis and a number of p53 mutants have “Gain of Function” (GOF) properties that have been shown to promote invasive and more aggressive phenotypes in cancer cells. Mutant p53 has been an attractive and promising therapeutic target for advanced stages of tumors. Further understanding the GOF properties of mutant p53 may help with design of novel strategies to target mutant p53 and/or key GOF pathways. We developed a novel functional high throughput screening (HTS) assay to identify miRNAs that selectively target GOF in mutant p53-expressing cell lines. Of the 2754 miRNA mimics screened, we identified 56 miRNAs that selectively reduced cell viability in TP53 R175H (mutant) cells. The current study characterizes the role of our lead mimic, miR-3132 in mutant p53 cells. We found that expression of miR-3132 is lost in cancer cells and that miR-3132 expression is correlated to p53 status, with mutant p53 cells expressing lower levels of miR-3132 than those with wild-type p53. Restoring expression of miR-3132 via mimics induces anti-proliferative and pro-apoptotic effects in a broad panel of colorectal (CRC), breast and lung cancer cell lines. In addition, miR-3132 induces TRAIL-dependent cell death in mutant p53-expressing cells. All cell lines show potent upregulation of cleaved caspases -8, -9 and -3, at 72 hrs post transfection with miR-3132. DNA damaging agents and serum starvation endogenously increase mature miR-3132 levels in wild-type p53 cells. However, this increase is blunted in mutant p53 cells, indicating that p53 could have a role in modulating either the transcriptional or post-transcriptional levels of miR-3132. In summary, we have identified miR-3132 as a TRAIL and cell death-inducing miRNA whose regulation is dependent on p53. Our ongoing work aims at finding the key targets of miR-3132 that explain the cellular response, TRAIL induction and subsequent cell death. Our long-term goal is to develop miR-3132 as a novel single or combinatorial anti-cancer agent for mutant p53 cancer cells. Citation Format: Amriti R. Lulla, Margret B. Einarson, Yan Zhou, Avital Lev, David T. Dicker, Wafik S. El-Deiry. miR-3132 induces TRAIL and cell death in mutant p53-expressing cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3908.