NO donor and MEK inhibitor synergistically inhibit proliferation and invasion of cancer cells

Abstract

Abstract.Nitric oxide (NO) shows tumoricidal activity. We had previously reported that NO downregulates the phosphatidylinositol-3-kinase/Akt pathway, but upregulates the MEK/ERK pathway downstream of growth factor signaling. We hypothesized that NO donor and MEK inhibitor in combination synergistically inhibit the viability of cancer cells compared to either NO donor or MEK inhibitor alone. We determined the effects of S-nitrosoglutathione (GSNO, NO-donor) and U0126 (MEK inhibitor) on insulin-like growth factor-I (IGF-I) and epidermal growth factor (EGF) signaling, proliferation and invasion in cancer cell lines. GSNO inhibits phosphorylation of IGF-I receptor (IGF-IR), EGF receptor (EGFR) and Akt, but upregulates ERK1/2 phosphorylation in MIAPaCa-2 and HCT-116 cells after stimulation by IGF-I and EGF. On the other hand, U0126 inhibits phosphorylation of ERK1/2, but upregulates phosphorylation of IGF-IR and EGFR in MIAPaCa-2 and HCT-116 cells. The combination of GSNO and U0126 downregulates phosphorylation of IGF-IR, EGFR, Akt and ERK1/2 after stimulation by IGF-I and EGF. GSNO as well as U0126, inhibits the proliferation of MIAPaCa-2, HCT-116, Panc-1, MCF-7, HT-29 and AGS cells in a dose-dependent manner. GSNO and U0126 in combination synergistically inhibit proliferation and invasion of cancer cells. These results indicate that the combined treatment of NO donor and MEK inhibitor may be promising in cancer therapy.

Epidermal growth factor (EGF) and interleukin (IL)-1β synergistically promote ERK1/2-mediated invasive breast ductal cancer cell migration and invasion

“…Growth factors can activate ERK1/2, and ERK1/2 activation is closely related to cancer cell migration and invasion, which may be regulated by the upstream kinase MEK1/2 via the growth factor-induced metastasis-associated pathway [23]. Therefore, we investigated the function of the representative growth factor, EGF and ERK1/2 signaling, in IBDC cells.…”

“…ERK1/2 are important regulators of progression and metastasis in a variety of cancers via the MEK/ERK/AP-1 signaling pathway [23,28]. However, it remains unknown as to whether ERK1/2 plays a role in IBDC metastasis.…”

S-Nitrosylation: An Emerging Paradigm of Redox Signaling

“…GSNO is generated in the mitochondria when the nitrosyl group is transferred from the heme iron of cytochrome c to glutathione (GSH) [96]. GSNO then translocates to different subcellular locales and transnitrosylates the interacting proteins including NF-κB, STAT3, AKT, EGFR, and IGF-1R [97,98,99]. GSNO-mediated transnitrosylation of the p65 and p50 subunits of NF-κB, as well as IκB kinase, inhibits NF-κB activation that is closely associated with malignant behavior of cancers [100,101,102].…”

“…STAT3, downstream of NF-κB, is also targeted for transnitrosylation by GSNO, which inhibits STAT3 phosphorylation required for its activation [101]. Additionally, cell surface receptors and the associated proteins, such as AKT, EGFR, and IGF-1R, are transnitrosylated by GSNO, leading to inhibition of their phosphorylation-dependent activation [99]. Accordingly, preclinical studies have reported the potent anti-cancer effects of GSNO in suppressing tumor cell growth and improving the efficacy of radiation therapy [98,101].…”

Glutathione S-conjugates as prodrugs to target drug-resistant tumors

“…GSNO promotes NO-induced apoptosis in colon carcinoma cell lines through depletion of intracellular GSH and the release of NO, (Ho et al, 1999; Liu et al, 2003). In a variety of cell lines, GSNO treatment combined with a MEK inhibitor was shown to inhibit the proliferation and invasive phenotype of the cells (Furuhashi et al, 2012). In T and B lymphocytes the anti-proliferative effect of GSNO was dependent on γGT activity (Henson et al, 1999).…”