Tonantzitlolone cytotoxicity toward renal cancer cells is PKCθ- and HSF1-dependent.
Tonantzitlolone cytotoxicity toward renal cancer cells is PKCθ- and HSF1-dependent.
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DOI：
10.18632/oncotarget.4676
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发表时间：
2015-10-06
期刊：
影响因子：
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通讯作者：
Neckers L
中科院分区：
文献类型：
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作者：
Sourbier C;Scroggins BT;Mannes PZ;Liao PJ;Siems K;Wolf D;Beutler JA;Linehan WM;Neckers L
在药物开发和评估潜在临床应用之前，阐明天然产物的作用靶点和机制具有重要的战略意义。本文阐述了天然产物托坦齐洛龙（TZL）治疗肾透明细胞癌（CCRCC）的主要靶点和作用机制。我们在体外鉴定TZL为PKCα和PKCθ的双重激活剂，尽管在CCRCC细胞中其活性主要是PKCθ依赖性的。TZL通过激活PKCθ，抑制IRS 1和PI 3 K/Akt通路，诱导胰岛素抵抗表型。同时，TZL激活热休克因子1（HSF 1）转录因子驱动葡萄糖依赖性。因此，与选择性PKCθ激活剂englerin A类似，TZL在CCRCC中诱导代谢灾难，使细胞缺乏葡萄糖，同时增加其糖酵解依赖性。
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.