Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN.
Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN.
J Lipid Res. 2013 Mar;54(3):776-785. doi: 10.1194/jlr.M033811. Epub 2013 Jan 14.
Fatty acid synthase (FASN) is a key enzyme in the synthesis of palmitate, the precursor of major nutritional, energetic, and signaling lipids. FASN expression is upregulated in many human cancers and appears to be important for cancer cell survival. Overexpression of FASN has also been found to associate with poor prognosis and higher risk of recurrence of human cancers. Indeed, elevated FASN expression has been shown to contribute to drug resistance. However, the mechanism of FASN-mediated drug resistance is currently unknown. In this study, we show that FASN overexpression causes resistance to multiple anticancer drugs via inhibiting drug-induced ceramide production, caspase 8 activation, and apoptosis. We also show that FASN overexpression suppresses tumor necrosis factor-α production and nuclear factor-κB activation as well as drug-induced activation of neutral sphingomyelinase. Thus, TNF-α may play an important role in mediating FASN function in drug resistance.
脂肪酸合酶（FASN）是合成棕榈酸的关键酶，棕榈酸是主要营养物质、能量物质和信号脂质的前体。在许多人类癌症中，FASN 的表达上调，并且似乎对癌细胞存活很重要。FASN 的过表达也与人类癌症的预后不良和复发风险增加有关。事实上，已经表明升高的 FASN 表达有助于耐药性。然而，目前尚不清楚 FASN 介导的耐药性的机制。在这项研究中，我们表明 FASN 的过表达通过抑制药物诱导的神经酰胺产生、半胱天冬酶 8 的激活和细胞凋亡导致对多种抗癌药物的耐药性。我们还表明，FASN 的过表达抑制肿瘤坏死因子-α的产生和核因子-κB 的激活以及药物诱导的中性鞘磷脂酶的激活。因此，TNF-α可能在介导 FASN 功能中的药物耐药性方面发挥重要作用。
