Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
Department of Pharmaceutical Botany, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.
Molecules. 2022 Sep 5;27(17):5716. doi: 10.3390/molecules27175716.
Hypoxia-inducible factor-1α (HIF-1α) is a major transcriptional regulator that plays a crucial role in the hypoxic response of rapidly growing tumors. Overexpression of HIF-1α has been associated with breast cancer metastasis and poor clinical prognosis. Plumbagin, the main phytochemical from , exerts anticancer effects via multiple mechanisms. However, its precise mechanisms on breast cancer cells under hypoxic conditions has never been investigated. This study aims to examine the anticancer effect of plumbagin on MCF-7 cell viability, transcriptional activity, and protein expression of HIF-1α under normoxia and hypoxia-mimicking conditions, as well as reveal the underlying signaling pathways. The results demonstrate that plumbagin decreased MCF-7 cell viability under normoxic conditions, and a greater extent of reduction was observed upon exposure to hypoxic conditions induced by cobalt chloride (CoCl). Mechanistically, MCF-7 cells upregulated the expression of HIF-1α protein, mRNA, and the VEGF target gene under CoCl-induced hypoxia, which were abolished by plumbagin treatment. In addition, inhibition of HIF-1α and its downstream targets did not affect the signaling transduction of the PI3K/Akt/mTOR pathway under hypoxic state. This study provides mechanistic insight into the anticancer activity of plumbagin in breast cancer cells under hypoxic conditions by abolishing HIF-1α at transcription and post-translational modifications.
缺氧诱导因子-1α（HIF-1α）是一种主要的转录调节因子，在快速生长肿瘤的缺氧反应中发挥关键作用。HIF-1α 的过表达与乳腺癌转移和不良临床预后有关。白花丹素是 的主要植物化学物质，通过多种机制发挥抗癌作用。然而，它在缺氧条件下对乳腺癌细胞的确切作用从未被研究过。本研究旨在研究白花丹素在常氧和缺氧模拟条件下对 MCF-7 细胞活力、转录活性和 HIF-1α 蛋白表达的抗癌作用，并揭示潜在的信号通路。结果表明，白花丹素在常氧条件下降低 MCF-7 细胞活力，而在钴氯化物（CoCl）诱导的缺氧条件下观察到更大程度的降低。在机制上，MCF-7 细胞在 CoCl 诱导的缺氧下上调 HIF-1α 蛋白、mRNA 和 VEGF 靶基因的表达，而白花丹素处理则消除了这种表达。此外，在缺氧状态下，抑制 HIF-1α 及其下游靶标并不影响 PI3K/Akt/mTOR 信号通路的信号转导。本研究通过在转录和翻译后修饰水平上消除 HIF-1α，为白花丹素在缺氧条件下对乳腺癌细胞的抗癌活性提供了机制上的见解。
