Abstract 3202: Deciphering the targets and mechanism of action of the natural product Tonantzitlolone in clear cell renal cell carcinomas

Abstract

Tonantzitlolone is a diterpene ester first extracted in 1990 from the native Mexican plant Stillingia sanguinolutea (Euphorbiaceae), which displays anti-tumor activity. Although its structure and total synthesis have been elucidated, its cellular target(s) and potential mechanism of action remain unknown. We identified Tonantzitlolone as a dual PKCα and PKCθ activator in vitro. However in clear cell renal cell carcinoma (CCRCC), its activity was mostly PKCθ-dependent. Through activation of PKCθ, Tonantzitlolone induced an insulin-resistant phenotype by inhibiting IRS1 and the PI3K/Akt pathway. Simultaneously, Tonantzitlolone activated the transcription factor heat shock factor 1 (HSF1), driving glucose dependency. Thus, similar to the selective PKCθ activator Englerin A, Tonantzitlolone induces a metabolic catastrophe in CCRCC, starving the cells of glucose while increasing their glycolytic dependency, ultimately leading to cell death. Citation Format: Carole Sourbier, Brad Scroggins, Philip Z. Mannes, John A. Beutler, W. Marston Linehan, Len Neckers. Deciphering the targets and mechanism of action of the natural product Tonantzitlolone in clear cell renal cell carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3202. doi:10.1158/1538-7445.AM2014-3202