Oncotarget

Research Papers:

Tonantzitlolone cytotoxicity toward renal cancer cells is PKCθ- and HSF1-dependent

Carole Sourbier _, Bradley T. Scroggins, Philip Z. Mannes, Pei-Jyun Liao, Karsten Siems, Dietmar Wolf, John A. Beutler, W. Marston Linehan and Leonard Neckers

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Oncotarget. 2015; 6:29963-29974. https://doi.org/10.18632/oncotarget.4676

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Abstract

Carole Sourbier1, Bradley T. Scroggins2, Philip Z. Mannes1, Pei-Jyun Liao1, Karsten Siems3, Dietmar Wolf3, John A. Beutler4, W. Marston Linehan1, Leonard Neckers1

1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA

2Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA

3AnalytiCon Discovery GmbH, D-14473 Potsdam, Germany

4Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA

Correspondence to:

Leonard Neckers, e-mail: neckersl@mail.nih.gov

Keywords: englerin A, bryostatin, renal tumors, RCC, PKCθ

Received: March 23, 2015     Accepted: July 10, 2015     Published: July 20, 2015

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.


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