Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Cancer Prev Res (Phila). 2018 Jun;11(6):337-346. doi: 10.1158/1940-6207.CAPR-17-0389. Epub 2018 Mar 15.
We have shown previously that dietary administration of phenethyl isothiocyanate (PEITC), a small molecule from edible cruciferous vegetables, significantly decreases the incidence of poorly differentiated prostate cancer in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice without any side effects. In this study, we investigated the role of c-Myc-regulated glycolysis in prostate cancer chemoprevention by PEITC. Exposure of LNCaP (androgen-responsive) and 22Rv1 (castration-resistant) human prostate cancer cells to PEITC resulted in suppression of expression as well as transcriptional activity of c-Myc. Prostate cancer cell growth inhibition by PEITC was significantly attenuated by stable overexpression of c-Myc. Analysis of the RNA-Seq data from The Cancer Genome Atlas indicated a significant positive association between expression and gene expression of many glycolysis-related genes, including and Expression of these enzyme proteins and lactate levels were decreased upon PEITC treatment in prostate cancer cells, and these effects were significantly attenuated by ectopic expression of c-Myc. A normal prostate stromal cell line (PrSC) was resistant to lactic acid suppression by PEITC treatment. Prostate cancer chemoprevention by PEITC in TRAMP mice was associated with a significant decrease in plasma lactate and pyruvate levels. However, a 1-week intervention with 10 mg PEITC (orally, 4 times/day) was not sufficient to decrease lactate levels in the serum of human subjects. These results indicated that although prostate cancer prevention by PEITC in TRAMP mice was associated with suppression of glycolysis, longer than 1-week intervention might be necessary to observe such an effect in human subjects. .
我们之前已经表明，食用十字花科蔬菜中的小分子苯乙基异硫氰酸酯（PEITC）可以显著降低转染性腺癌小鼠前列腺（TRAMP）小鼠中低分化前列腺癌的发病率，而没有任何副作用。在这项研究中，我们研究了 PEITC 通过 c-Myc 调节的糖酵解在前列腺癌化学预防中的作用。暴露于 PEITC 的 LNCaP（雄激素反应）和 22Rv1（去势抵抗）人前列腺癌细胞导致 c-Myc 的表达和转录活性受到抑制。c-Myc 稳定过表达显著减弱了 PEITC 对前列腺癌细胞生长的抑制作用。来自癌症基因组图谱的 RNA-Seq 数据分析表明，在许多与糖酵解相关的基因的表达中，包括 和 ，表达与 c-Myc 的表达之间存在显著的正相关。PEITC 处理可降低前列腺癌细胞中这些酶蛋白的表达和乳酸水平，而 c-Myc 的异位表达则显著减弱了这些作用。正常前列腺基质细胞系（PrSC）对 PEITC 处理导致的乳酸抑制具有抗性。PEITC 在 TRAMP 小鼠中的前列腺癌化学预防与血浆乳酸和丙酮酸水平的显著降低有关。然而，为期 1 周的 10mg PEITC（口服，每日 4 次）干预不足以降低人类受试者血清中的乳酸水平。这些结果表明，尽管 PEITC 在 TRAMP 小鼠中的前列腺癌预防与糖酵解的抑制有关，但在人类中观察到这种效果可能需要超过 1 周的干预。
