Abstract
Aberrations within the phosphoinositide-3-kinase (PI3K) pathway occur in greater than 45% of ovarian carcinomas. The PI3K cascade transmits signals from ErbB receptors downstream to S6 and 4EBP1, which are involved in protein biosynthesis. Many ovarian carcinomas reveal hyperactivation of ErbB1 (epidermal growth factor receptor) or ErbB2 (HER2/neu). Unfortunately, the benefit of anti-ErbB drugs is yet rather limited in ovarian carcinomas. Thus, novel targeting strategies are needed for ovarian carcinomas. The lipogenic enzyme fatty acid synthase (FASN) is overexpressed in approximately 80% of ovarian carcinomas. It stimulates cell growth and signifies poor prognosis. FASN inhibition impedes (ErbB) membrane receptor signaling and sensitizes cells against anti-ErbB drugs. Here, we show that the FASN inhibitor C75 and FASN-targeting siRNAs abrogate growth, induce apoptosis, and downregulate phosphorylation/expression of the PI3K effectors AKT, mTOR, p70S6K, S6, and 4EBP1. In contrast, FASN inhibition impairs expression but only weakly affects phosphorylation of ERK1/2 mitogen-activated protein kinases in ovarian carcinoma cells. Cycloheximide-mediated blockade of protein translation reveals that C75- or FASN siRNA-induced shutdown of FASN accelerates decomposition of signaling proteins. This effect is caused by C75- or FASN siRNA-dependent stimulation of ubiquitination followed by lysosomal-autophagosomal proteolysis. In contrast, PI3K inhibitor LY294002 blocks phosphorylation but does not reduce expression/stability of PI3K effectors. Forced expression of hyperactive (HA) AKT1, unlike HA-MEK1, impairs the growth-inhibitory action of C75. We provide first evidence that the anticancer action of FASN inhibitors is at least partially mediated by drug-dependent proteolysis of PI3K effectors. FASN is a promising cancer target, whose inhibition not only abrogates lipogenesis, which is indispensable for cancer growth, but also downregulates oncogenic PI3K signaling.
Highlights
The phosphoinositide-3-kinase (PI3K) signaling cascade controls many cellular functions including proliferation, differentiation, tumorigenesis, angiogenesis, autophagy, and apoptosis
The S6 protein is a component of the 40S ribosomal subunit, which is required for the synthesis of polypeptides at the ribosome. 4E (eIF4E) inhibitor–binding protein 1 (4EBP1), on the other hand, modulates the function of eukaryotic translation initiation factor 4E (eIF4E), which is involved in cap-dependent translation of growth-promoting genes
Using in vitro growth assays and Western blot analyses, we examined the effects of C75 on cell growth, on apoptosis, on PI3K and mitogen-activated protein kinase (MAPK) signaling pathways, and on protein ubiquitination in a panel of additional ovarian carcinoma cell lines (OVCAR-3, SKOV-3, and HEY)
Summary
The phosphoinositide-3-kinase (PI3K) signaling cascade controls many cellular functions including proliferation, differentiation, tumorigenesis, angiogenesis, autophagy, and apoptosis. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). Molecular aberrations within the PI3K system including, for instance, PI3K itself, AKT, mTOR, and p70S6K [1, 2]. The core route of the pathway from PI3K to AKT and mTOR diverges at mTOR [3], which activates either p70S6K and ribosomal protein S6 or the eukaryotic translation initiation factor 4E (eIF4E) inhibitor–binding protein 1 (4EBP1). Both S6 and 4EBP1 are involved in protein synthesis [4]
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