title: Tonantzitlolone cytotoxicity toward renal cancer cells is PKCθ- and HSF1-dependent.
abstract: 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.
authors: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Carole
authors: C
authors: Sourbier
authors: Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Bradley T
authors: BT
authors: Scroggins
authors: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Philip Z
authors: PZ
authors: Mannes
authors: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Pei-Jyun
authors: PJ
authors: Liao
authors: AnalytiCon Discovery GmbH, D-14473 Potsdam, Germany.
authors: Karsten
authors: K
authors: Siems
authors: AnalytiCon Discovery GmbH, D-14473 Potsdam, Germany.
authors: Dietmar
authors: D
authors: Wolf
authors: Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
authors: John A
authors: JA
authors: Beutler
authors: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors: W Marston
authors: WM
authors: Linehan
authors: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Leonard
authors: L
authors: Neckers
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D057809:HEK293 Cells; D000076249:Heat Shock Transcription Factors; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D034622:RNA Interference; D045789:Sesquiterpenes, Guaiane / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004224:Diterpenes; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D007527:Isoenzymes; D047028:Macrocyclic Compounds; D045789:Sesquiterpenes, Guaiane; D014157:Transcription Factors; C534971:englerin A; C510266:tonantzitlolone; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D005947:Glucose
keywords: PKCθ; RCC; bryostatin; englerin A; renal tumors