tonantzitlolone and Kidney-Neoplasms

Elucidating the targets and mechanism of action of natural products is strategically important prior to drug development and assessment of potential clinical applications. In this report, we elucidated the main targets and mechanism of action of the natural product tonantzitlolone (TZL) in clear cell renal cell carcinoma (CCRCC). We identified TZL as a dual PKCα and PKCθ activator in vitro, although in CCRCC cells its activity was mostly PKCθ-dependent. Through activation of PKCθ, TZL induced an insulin resistant phenotype by inhibiting IRS1 and the PI3K/Akt pathway. Simultaneously, TZL activated the heat shock factor 1 (HSF1) transcription factor driving glucose dependency. Thus, similar to the selective PKCθ activator englerin A, TZL induces a metabolic catastrophe in CCRCC, starving cells of glucose while simultaneously increasing their glycolytic dependency.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Survival; Diterpenes; DNA-Binding Proteins; Dose-Response Relationship, Drug; Enzyme Activation; Glucose; Heat Shock Transcription Factors; HEK293 Cells; Humans; Immunoblotting; Isoenzymes; Kidney Neoplasms; Macrocyclic Compounds; Molecular Structure; Phosphorylation; Protein Kinase C; Protein Kinase C-theta; RNA Interference; Sesquiterpenes, Guaiane; Transcription Factors