Abstract 4474: Dual targeting of the stress-p53 pathway as a potential anti-cancer therapy

The “ribosomal stress (RS)-p53 pathway” is triggered by any stressor or genetic alteration that disrupts ribosomal biogenesis, and mediated by several ribosomal proteins (RPs), such as RPL11 and RPL5, which inhibit MDM2 and activate p53. IMPDH2 is a rate-limiting enzyme in de novo guanine nucleotide biosynthesis and crucial for maintaining cellular guanine deoxy- and ribonucleotide pools needed for DNA and RNA synthesis. It is highly expressed in many malignancies. We previously showed that inhibition of IMPDH2 leads to p53 activation by causing RS. Surprisingly, our current study reveals that Inauzhin (INZ), a novel non-genotoxic p53 activator by inhibiting SIRT1, can also inhibit cellular IMPDH2 activity, and reduce the levels of cellular GTP and GTP-binding nucleostemin that is essential for rRNA processing. Consequently, INZ induces RS and the RPL11/RPL5-MDM2 interaction, activating p53. These results support the new notion that INZ suppresses cancer cell growth by dually targeting SIRT1 and IMPDH2. Note: This abstract was not presented at the meeting. Citation Format: Hua Lu, Qi Zhang, Shelya X. Zeng, Rui-Zhi Wu, Yiwei Zhang, Daniel Nguyen, Xiang Zhou, Jun-ming Liao, Bo Cao. Dual targeting of the stress-p53 pathway as a potential anti-cancer therapy. [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 4474. doi:10.1158/1538-7445.AM2015-4474