Department of Translational Pharmacology, Laboratory of Signal-Dependent Transcription, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.
Int J Gynecol Cancer. 2010 Feb;20(2):203-11. doi: 10.1111/igc.0b013e3181c8ca12.
Ovarian cancer is highly sensitive to chemotherapy but also shows a high rate of recurrence and drug resistance. These negative outcomes mostly depend on altered apoptotic pathways, making the design of new therapeutic strategies based on the induction of other types of cell death highly desirable. Several lines of research are now addressing cancer-specific features to specifically target tumor cells, thus reducing adverse effects. In this light, a great deal of attention has been devoted to the metabolic reprogramming occurring in cancer cells, which display increased levels of glycolysis compared with their normal counterparts. We recently showed that inhibition of p38alpha impairs key metabolic functions of colorectal cancer cells, inducing growth arrest, autophagy, and cell death both in vivo and in vitro. These effects are mediated by a switch from hypoxia-inducible factor 1alpha (HIF1alpha) to forkhead transcription factor O (FoxO)-dependent transcription.
We first characterized p38 expression in OVCAR-3, A2780, and SKOV-3 ovarian cancer cell lines. Then, we treated these cells with the p38alpha/p38beta-specific inhibitor SB202190 and performed a morphological, proliferation, and survival analyses. Finally, we studied HIF1alpha and FoxO3A expressions and signaling pathways to evaluate their role in SB202190-induced effects.
p38alpha blockade induces the formation of intracellular autophagic vacuoles and reduces growth and viability of ovarian cancer cells. As in colorectal cancer, the underlying molecular mechanism seems to rely on a shift from HIF1alpha- to FoxO3A-dependent transcription, which is promoted by the activation of the adenosine monophosphate-activated protein kinase pathway.
These data corroborate the hypothesis that pharmacological modulation of genes involved in cancer-specific homeostasis, such as p38alpha, might be exploited to design new therapeutic approaches to cancer treatment.
卵巢癌对化疗高度敏感，但也表现出高复发率和耐药性。这些负面结果主要取决于凋亡途径的改变，因此非常需要设计基于诱导其他类型细胞死亡的新治疗策略。现在有几条研究线针对癌症特有的特征，以专门针对肿瘤细胞，从而减少不良反应。在这方面，人们非常关注癌细胞中发生的代谢重编程，与正常细胞相比，癌细胞的糖酵解水平升高。我们最近表明，抑制 p38alpha 会损害结直肠癌细胞的关键代谢功能，在体内和体外诱导生长停滞、自噬和细胞死亡。这些作用是通过从缺氧诱导因子 1alpha (HIF1alpha) 到叉头转录因子 O (FoxO) 依赖性转录的转换介导的。
我们首先在 OVCAR-3、A2780 和 SKOV-3 卵巢癌细胞系中表征 p38 的表达。然后，我们用 p38alpha/p38beta 特异性抑制剂 SB202190 处理这些细胞，并进行形态学、增殖和存活分析。最后，我们研究了 HIF1alpha 和 FoxO3A 的表达和信号通路，以评估它们在 SB202190 诱导的作用中的作用。
p38alpha 阻断诱导细胞内自噬空泡的形成，并减少卵巢癌细胞的生长和活力。与结直肠癌一样，潜在的分子机制似乎依赖于从 HIF1alpha 到 FoxO3A 依赖性转录的转变，这是由腺苷单磷酸激活蛋白激酶途径的激活所促进的。
这些数据支持了这样一种假设，即通过药理学调节参与癌症特异性稳态的基因，如 p38alpha，可以被利用来设计新的癌症治疗方法。
