BIO5 Institute, University of Arizona, Tucson, AZ, United States of America.
Department of Biology, University of Louisville, Louisville, KY, United States of America.
PLoS One. 2023 Mar 9;18(3):e0281396. doi: 10.1371/journal.pone.0281396. eCollection 2023.
Hypoxia is a common feature of most solid tumors, one that favors tumor progression and limits treatment effectiveness. Targeting hypoxia has long been a goal in cancer therapy, by identifying factors that reverse or ameliorate the effects of hypoxia on cancer cells. We, and others, have shown that β-caryophyllene (BCP) exhibits anti-proliferative properties in cancer cells. We have further shown that non-cytotoxic concentrations of BCP affect cholesterol and lipid biosynthesis in hypoxic hBrC cells at both transcriptional and translational levels. This led us to hypothesize that BCP may reverse the hypoxic phenotype in hBrC cells. To test this, we determined the effect of BCP on hypoxic sensitive pathways, including oxygen consumption, glycolysis, oxidative stress, cholesterol and fatty acid biosynthesis, and ERK activation. While each of these studies revealed new information on the regulation by hypoxia and BCP, only the lipidomic studies showed reversal of hypoxic-dependent effects by BCP. These later studies showed that hypoxia-treated samples lowered monounsaturated fatty acid levels, shifting the saturation ratios of the fatty acid pools. This signature was ameliorated by sub-lethal concentrations of BCP, possibly through an effect on the C:16 fatty acid saturation ratios. This is consistent with BCP-induced upregulation of the stearoyl-CoA desaturase (SCD) gene, observed previously. This suggests that BCP may interfere with the lipid signature modulated by hypoxia which could have consequences for membrane biosynthesis or composition, both of which are important for cell replication.
缺氧是大多数实体瘤的共同特征，它有利于肿瘤的进展，并限制了治疗的效果。靶向缺氧一直是癌症治疗的目标，通过确定可以逆转或减轻缺氧对癌细胞影响的因素来实现。我们和其他人已经表明，β-石竹烯（BCP）在癌细胞中表现出抗增殖特性。我们进一步表明，非细胞毒性浓度的 BCP 会在转录和翻译水平上影响缺氧 hBrC 细胞中的胆固醇和脂质生物合成。这使我们假设 BCP 可能逆转 hBrC 细胞中的缺氧表型。为了验证这一点，我们确定了 BCP 对缺氧敏感途径的影响，包括耗氧量、糖酵解、氧化应激、胆固醇和脂肪酸生物合成以及 ERK 激活。虽然这些研究中的每一项都揭示了关于缺氧和 BCP 调节的新信息，但只有脂质组学研究显示 BCP 逆转了缺氧依赖性效应。这些后续研究表明，缺氧处理的样本降低了单不饱和脂肪酸水平，使脂肪酸池的饱和度比率发生变化。亚致死浓度的 BCP 可改善这种情况，可能是通过对 C：16 脂肪酸饱和度比率的影响。这与之前观察到的 BCP 诱导硬脂酰辅酶 A 去饱和酶（SCD）基因上调一致。这表明 BCP 可能干扰由缺氧调节的脂质特征，这可能对膜生物合成或组成产生影响，这两者对于细胞复制都很重要。
