The anti-tumor activator sMEK1 and paclitaxel additively decrease expression of HIF-1α and VEGF via mTORC1-S6K/4E-BP-dependent signaling pathways

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.

Suppression of the proliferation of hypoxia‐Induced retinal pigment epithelial cell by rapamycin through the /mTOR/HIF‐1α/VEGF/ signaling

“…The pathway of mTOR signaling plays an important part in the expression of HIF-1a and VEGF. mTORC1 pathway has been shown to regulate the synthesis of HIF-1a at the translational level (17,18,21), consistent with our finding that rapamycin did not alter HIF-1a mRNA expression. We also showed that rapamycin markedly inhibited the phosphorylation of mTOR, P70S6K, and 4E-BP1 and the expression of HIF-1a and VEGF in REP cells exposed to hypoxia, suggesting that under hypoxic condition, the mTOR/ P70S6K/4E-BP1 pathway is crucial in rapamycin-mediated inhibition of HIF-1a and VEGF in RPE cells.…”

Low-Dose Paclitaxel Reduces S100A4 Nuclear Import to Inhibit Invasion and Hematogenous Metastasis of Cholangiocarcinoma

“…While these mechanisms of action are well evident at the conventional doses, at the much lower doses used in the current study, they do not seem to occur. Recent studies performed in ovarian carcinoma cells indicate that alternatively, PTX may inhibit the expression of other critical molecular factors of tumor progression, such as hypoxia-inducible factor-1α and vascular endothelial growth factor (35). …”

Bufalin reverses intrinsic and acquired drug resistance to cisplatin through the AKT signaling pathway in gastric cancer cells

“…Hypoxia-induced AKT activation has been elucidated in a number of types of cancer (36). Reportedly, AKT activation increases expression of HIF-1α (13,18,19), which in turn aggravates hypoxia. This indicates positive feedback, whereby In conclusion, the present results indicate that administering cisplatin in combination with bufalin may overcome or delay resistance to cisplatin and extend the efficacy of cisplatin in treating GC, thus suggesting a novel strategy for treatment of advanced GC to be investigated further in clinical trials.…”

“…Hypoxia-inducible factor (HIF)-1α is a fundamental driver of cellular adaptation to hypoxia (14,17). Reportedly, the PI3K/AKT pathway activation upregulates HIF-1α expression (13,18,19), which contributes to cisplatin resistance in GC cells (13,14). It was therefore suggested that AKT may be central to intrinsic and acquired cisplatin resistance in GC.…”