Fonseca Joao, Moradi Fereshteh, Maddalena Lucas A, Ferreira-Tollstadius Bruna, Selim Shehab, Stuart Jeffrey A
Department of Biological Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada.
MRC Cancer Research Centre, University of Cambridge, Hutchison/MRC Research Centre, Cambridge CB2 0XZ, United Kingdom.
Oncol Lett. 2019 Jan;17(1):697-705. doi: 10.3892/ol.2018.9526. Epub 2018 Sep 28.
Resveratrol (RES) is a polyphenol produced by certain plant species that has been well studied due to its ability to slow the growth of cancer cells. In numerous cell types and tissues, RES has been demonstrated to promote mitochondrial biogenesis, fusion, and oxidative phosphorylation. The present study investigated the interaction between RES's effects on growth and metabolism in PC3 prostate cancer cells, and demonstrated that RES-mediated growth inhibition is only observed under conditions in which a metabolic shift from glucose fermentation to mitochondrial respiration can occur. When this shift was prevented by growing cells in galactose medium or by pharmacologically inhibiting prolyl hydroxylase (PHD) in order to stabilize hypoxia inducible factor-1α, RES did not effect mitochondrial fusion, biogenesis, respiration or cell growth. Similar results were observed in PC3 cells expressing a mutant HIF-1α lacking the prolines that are hydroxylated by PHD to promote its degradation. Thus, RES appears to slow PC3 cell growth by interfering with glucose fermentation and promoting respiration. Consistent with this, RES was observed to be particularly effective at inhibiting PC3 cell growth under hypoxic conditions that precluded increased reliance on oxidative phosphorylation. These observations are important in understanding how RES may affect cancer cell growth where hypoxia is common in growing tumours.
白藜芦醇（RES）是某些植物产生的一种多酚，因其具有减缓癌细胞生长的能力而得到了充分研究。在众多细胞类型和组织中，RES已被证明可促进线粒体生物发生、融合及氧化磷酸化。本研究调查了RES对PC3前列腺癌细胞生长和代谢影响之间的相互作用，并证明只有在能够发生从葡萄糖发酵到线粒体呼吸的代谢转变的条件下，才会观察到RES介导的生长抑制。当通过在半乳糖培养基中培养细胞或通过药理学抑制脯氨酰羟化酶（PHD）以稳定缺氧诱导因子-1α来阻止这种转变时，RES对线粒体融合、生物发生、呼吸或细胞生长没有影响。在表达缺乏被PHD羟化以促进其降解的脯氨酸的突变型HIF-1α的PC3细胞中也观察到了类似结果。因此，RES似乎通过干扰葡萄糖发酵和促进呼吸来减缓PC3细胞生长。与此一致的是，在缺氧条件下，即排除了对氧化磷酸化增加依赖的情况下，观察到RES在抑制PC3细胞生长方面特别有效。这些观察结果对于理解RES在肿瘤生长中常见缺氧的情况下如何影响癌细胞生长具有重要意义。
