Abstract
Recently, we found that sMEK1 effectively regulates pro-apoptotic activity when combined with a traditional chemotherapeutic drug. Therefore, combinational therapeutic strategies targeting critical molecular and cellular mechanisms are urgently required. In this present work, we evaluated whether sMEK1 enhanced the pro-apoptotic activity of chemotherapeutic drugs in ovarian carcinoma cells. Combined with a chemotherapeutic drug, sMEK1 showed an additive effect on the suppression of ovarian cancer cell growth by inducing cell cycle arrest and apoptosis and regulating related gene expression levels or protein activities. In addition, the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was strongly inhibited by the combined treatment, showing de-repression of the tuberous sclerosis complex (TSC) and suppression of ras homolog enriched in the brain (Rheb) and mTOR and raptor in aggressive ovarian carcinoma cells and mouse xenograft models. Treatment with sMEK1 and paclitaxel reduced phosphorylation of ribosomal S6 kinase (S6K) and 4E-binding protein (4E-BP), two critical downstream targets of the mTOR-signaling pathway. Furthermore, both sMEK1 and paclitaxel significantly inhibited the expression of signaling components downstream of S6K/4E-BP, such as hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF), both in vitro and in vivo. Therefore, our data suggest that the combination of sMEK1 and paclitaxel is a promising and effective targeted therapy for chemotherapy-resistant or recurrent ovarian cancers.
Highlights
Ovarian cancer shows the highest mortality rates of all malignant gynecologic tumors, and its prognosis is very poor
Our results suggest that sMEK1 has a novel biological function; i.e., further activation of paclitaxelstimulated apoptosis via the concomitant inhibition of the Akt-ras homolog enriched in the brain (Rheb) and mTOR complex 1 (mTORC1)-S6 kinase (S6K)/4E-binding protein (4E-BP) signaling pathways
Our data indicate that sMEK1 is an important modulator of mTORC1-dependent apoptotic cell death under physiological/biological conditions
Summary
Ovarian cancer shows the highest mortality rates of all malignant gynecologic tumors, and its prognosis is very poor. Paclitaxel is a powerful chemotherapeutic drug that binds to microtubules and prevents division in malignant ovarian, lung, breast, and prostate tumor cells [1, 2]. It acts through the induction of G2/M cell cycle arrest, with subsequent mitotic arrest and apoptosis [3]. Paclitaxel is considered one of the most clinically active chemotherapeutic drugs for the treatment of a variety of solid tumors, including gynecologic cancers [4, 5]. Apoptosis is an important mechanism of drug-stimulated cancer cell death, with the sensitivity to apoptosis of the various types of carcinoma cell being a major determinant of chemotherapy and radiation efficacy. Paclitaxel treatment itself can regulate the expression and mediate post-translational modifications of the Bcl-2 family proteins [9,10,11,12]
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