Argatroban The RAS RAF MEK ERK

The RAS/RAF/MEK/ERK pathway is a central controller of cell proliferation and survival and, consequently, alterations to some of its components lead to hyperactivation of the pathway, an event related to numerous types of cancer [172]. High rates of alterations to this pathway are found in leukemia, colorectal, pancreatic and lung cancers [173]. Moreover, synergistic activation of both RAS/RAF/MEK/ERK and Hedgehog pathways are reported in a diverse spectrum of malignancies [173]. Experimental evidence shows that co-activation of both pathways resulted in the formation of pancreatic intraepithelial neoplasias in a transgenic mouse model [174]. In another study, mice lacking Gli1 presented a reduced progression of KRAS-induced pancreatic preneoplastic lesions [175]. In pancreatic cancer cells, KRAS was shown to be capable of Hedgehog pathway activation via MEK/ERK1/2, increasing the levels and the transcriptional activity of Gli1 levels. This activation was blocked by siRNA targeted towards KRAS inhibition, or by pharmacological inhibition of MEK [176]. In addition, many studies have provided evidence of crosstalk between aberrant activation of the Hedgehog pathway and ERK1/2 in different types of cancer (see [177] for review). The PI3K/AKT/mTOR signaling pathway constitutes an important mechanisms that regulates numerous cellular processes such as growth, proliferation, differentiation and apoptosis [178]. Consequently, deregulation of this pathway favors the survival of cancer Argatroban and their proliferation and progression into cancer [179]. Additionally, treatment of HeLa cells with rapamycin, an inhibitor of mTORC1, has been shown to regulate nuclear localization and transcriptional activity of Gli3, suggesting a crosstalk between PI3K/AKT/mTOR and Hedgehog signaling [180]. A synergistic relationship was also reported between both pathways in embryonic development and in Hedgehog-dependent tumors [181]. Cooperation between PI3K/AKT and Hedgehog pathways has been shown to promote cancer cell survival, proliferation and metastasis in esophageal [182,183], pancreatic [3,184], soft-tissue sarcoma [185], or biliary tract cancer cells [186]. Another interesting study on immunohistochemical analysis of primary human gastric tumor biopsies found that activation of the Hedgehog pathway was directly correlated with lymph node metastasis through PI3K/Akt interaction [187]. The Wnt/β-catenin signaling pathway is involved in determination of cell fate and organ development during embryonic growth, but also participates in the regulation of tissue renewal in adults [188]. Alterations of the Wnt/β-catenin pathway and its components have been related to carcinogenesis mechanisms [[189], [190], [191]]. Moreover, signaling interference between Wnt and Hedgehog pathways has been found in gastric and prostatic cancer cells [192,193]. An over-expression of Gli1 in endometrial cancer cell lines leads to an increased expression of nuclear β-catenin, evidencing a direct interaction of Gli1 with β-catenin [194]. However, a great heterogeneity in gene expression and interactions in the activation of Wnt and Hedgehog pathways was found in stage III serous ovarian cancer [195]. These data suggest that such variability could be one of the main causes for drug resistance in this type of cancer. In addition to these signaling pathways, other pathways could also synergistically interact with the Hedgehog signaling pathway in different types of cancer. Among these signaling pathways, the androgen receptor [196], hypoxia inducible factor (HIF)-1〈 [197], interleukin (IL)-6/IL-6 r/gp130 [198] or transforming growth factor-beta TGFβ [199] pathways bear particular mention.
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Conflicts of interest statement
Acknowledgements The Indian author gratefully acknowledge the Bioinformatics Infrastructure Facility [BT/BI/25/015/2012, DBT, GoI] and RUSA 2.0 [F. 24-51/2014-U, Policy (TN Multi-Gen), Dept of Edn, GoI]. A. Sureda was supported by the Programme of Promotion of Biomedical Research and Health Sciences CIBEROBNCB12/03/30038.