Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India.
University of Massachusetts Medical School, USA.
Biochim Biophys Acta Mol Cell Res. 2024 Dec;1871(8):119805. doi: 10.1016/j.bbamcr.2024.119805. Epub 2024 Aug 17.
Epithelial ovarian cancer (EOC), a leading cause of gynecological cancer-related morbidity and mortality and the most common type of ovarian cancer (OC), is widely characterized by alterations in the Epidermal Growth Factor (EGF) signaling pathways. The phenomenon of metastasis is largely held accountable for the majority of EOC-associated deaths. Existing literature reports substantiate evidence on the indispensable role of metabolic reprogramming, particularly the phenomenon of the 'Warburg effect' or aerobic glycolysis in priming the cancer cells towards Epithelial to Mesenchymal transition (EMT), subsequently facilitating EMT. Considering the diverse roles of growth factor signaling across different stages of oncogenesis, our prime emphasis was laid on unraveling mechanistic details of EGF-induced 'Warburg effect' and resultant metastasis in EOC cells. Our study puts forth Ets1, an established oncoprotein and key player in OC progression, as the prime metabolic sensor to EGF-induced cues from the tumor microenvironment (TME). EGF treatment has been found to induce Ets1 expression in OC cells predominantly through the Extracellular Signal-Regulated Kinase1/2 (ERK1/2) pathway activation. This subsequently results in pronounced glycolysis, characterized by an enhanced lactate production through transcriptional up-regulation of key determinant genes of the central carbon metabolism namely, hexokinase 2 (HK2) and monocarboxylate transporter 4 (MCT4). Furthermore, this study reports an unforeseen combinatorial blockage of HK2 and MCT4 as an effective approach to mitigate cellular metastasis in OC. Collectively, our work proposes a novel mechanistic insight into EGF-induced glycolytic bias in OC cells and also sheds light on an effective therapeutic intervention approach exploiting these insights.
上皮性卵巢癌（EOC）是妇科癌症相关发病率和死亡率的主要原因，也是最常见的卵巢癌（OC）类型，其特征广泛表现为表皮生长因子（EGF）信号通路的改变。转移现象在很大程度上是导致大多数与 EOC 相关的死亡的原因。现有文献报告证实了代谢重编程的不可或缺的作用，特别是有氧糖酵解的“Warburg 效应”在促使癌细胞向上皮间质转化（EMT）方面起着关键作用，进而促进 EMT。考虑到生长因子信号在肿瘤发生的不同阶段具有多样化的作用，我们的主要重点是揭示 EGF 诱导的“Warburg 效应”和 EMT 在 EOC 细胞中的转移的机制细节。我们的研究提出 Ets1，一种已确立的癌蛋白，也是 OC 进展的关键参与者，作为对肿瘤微环境（TME）中 EGF 诱导信号的主要代谢传感器。EGF 处理已被发现主要通过细胞外信号调节激酶 1/2（ERK1/2）途径的激活来诱导 OC 细胞中的 Ets1 表达。这继而导致明显的糖酵解，其特征是通过转录上调中央碳代谢的关键决定基因，即己糖激酶 2（HK2）和单羧酸转运蛋白 4（MCT4），来增强乳酸的产生。此外，本研究报告了一种意想不到的 HK2 和 MCT4 的组合阻断作为减轻 OC 中细胞转移的有效方法。总的来说，我们的工作提出了一种新的机制见解，即 EGF 诱导 OC 细胞中的糖酵解偏向，并提出了利用这些见解的有效治疗干预方法。
