Inhibition of MAPK Kinase Signaling Pathways Suppressed Renal Cell Carcinoma Growth and Angiogenesis In vivo

Abstract

The mitogen-activated protein kinase (MAPK) signaling pathways play essential roles in cell proliferation and differentiation. Recent studies also show the activation of MAPK signaling pathways in tumorigenesis, metastasis, and angiogenesis of multiple human malignancies, including renal cell carcinoma (RCC). To assess the role of this pathway in regulating the proliferation and survival of RCC cells, we first examined the expression of MAPK kinase (MKK) and MAPK in clear cell RCC and confirmed the overexpression of MKK1 and extracellular signal-regulated kinase 2 (ERK2) in these tumors. We then tested the effects of pharmacologic inhibition of MKK on human RCC cell lines, both in vitro and in vivo, using anthrax lethal toxin (LeTx), which cleaves and inactivates several MKKs. Western blotting showed that the phosphorylation levels of ERK, c-Jun-NH 2 kinase, and p38 MAPK decreased after 72 h of LeTx treatment. Exposure to LeTx for 72 h reduced cell proliferation by 20% without significant effects on cell cycle distribution and apoptosis. Anchorageindependent growth of RCC cells was dramatically inhibited by LeTx. In vivo studies showed that tumor growth of RCC xenografts could be suppressed by LeTx. Extensive necrosis and decreased tumor neovascularization were observed after LeTx treatment. LeTx also showed direct inhibition of proliferation of endothelial cells in vitro. Our results suggest that suppression of one or more MAPK signaling pathways may inhibit RCC growth through the disruption of tumor vasculature. [Cancer Res 2008;68(1):81-8]

LIM-class homeobox gene Lim1, a novel oncogene in human renal cell carcinoma

“…Our group and other investigators have reported the critical role played by the oncogenic PI3K/Akt, NF-kB and MAPK signaling pathways as well as by the developmental Notch and SHH-Gli signaling in human CCC tumorigenesis (Sourbier et al, 2006Huang et al, 2008;Sjolund et al, 2008;Dormoy et al, 2009). In all cases, these pathways were shown to be constitutively activated and turned towards tumor growth regardless of VHL status.…”

“…The PI3K/Akt, NF-kB, MAPK, Notch and SHH signaling pathways are activated constitutively in human CCC (Sourbier et al, 2006Huang et al, 2008;Sjolund et al, 2008;Dormoy et al, 2009) strongly suggesting that tumor cells reactivate developmental pathways for their growth, invasion and immune escape. Here, we show that Lim1 regulates the activation of the oncogenic pathways PI3K/Akt, NF-kB and MAPK; and also regulates the expression and/or activity of a broad range of oncogenic pathways and molecular factors involved in cell apoptosis, proliferation and movements, and in angiogenesis processes.…”

“…More recently, we have reached similar conclusions concerning the involvement of the developmental sonic hedgehog (SHH) signaling pathway in human CCC progression, and we showed further that the SHH signaling pathway has orchestral roles in the activation of oncogenic pathways in this disease, including the phosphoinositide kinase-3 (PI3K)/ Akt, the nuclear factor-kappaB (NF-kB) and mitogenactivated protein kinase (MAPK) signaling pathways (Dormoy et al, 2009). This is particularly important as all these pathways, critical during kidney development (Reidy and Rosenblum, 2009), are constitutively reactivated in CCC tumors (Sourbier et al, 2006Schedl, 2007;Huang et al, 2008).…”

Eupatilin induces human renal cancer cell apoptosis via ROS-mediated MAPK and PI3K/AKT signaling pathways

“…In addition, the MAPK signaling pathway has a significant role in the regulation of a number of cellular processes, including cell growth and proliferation, differentiation, and apoptosis (16). Therefore, the present study investigated whether eupatilin was able to induce the activation of MAPK cascades in 786-O cells.…”

Barbigerone Inhibits Tumor Angiogenesis, Growth and Metastasis in Melanoma

“…Recent studies have shown the activation of MAPK signaling pathways including extracellular signal-regulated protein kinase (ERK), c-Jun amino-terminal kinases (JNK), and p38 MAPK (p38) in tumorigenesis, metastasis, and angiogenesis of multiple human malignancies (Huang et al, 2008).…”