Constitutive activation of the 41‐ and 43‐kDa mitogen‐activated protein (MAP) kinases in the progression of prostate cancer to an androgen‐independent state

Abstract

Aim : The 41-and 43-kDa mitogen-activated protein kinases (MAPK; ERK2 and ERK1, respectively) play pivotal roles in the mitogenic signal transduction pathway. We previously demonstrated that constitutive activation of the MAPK cascade was related to the carcinogenesis of human tumors. In this study, we examined whether constitutive activation of MAPK was related to the progression to androgen independence of prostate cancer. Methods : MAPK activation was examined by the appearance of phosphorylated forms and an in vitro kinase assay in four human (androgen-dependent and independent) prostate cancer cell lines and rat prostate cancer cell line Dunning (androgen-sensitive G line, and androgen-independent AT-3, AT-6 sublines). In addition, when androgen-dependent mouse Shionogi Carcinoma 115 (SC115) cells were serially cultured without androgen to obtain androgen-independent cells, the time and degree of MAPK activation were examined. Results : One of three human androgen-independent cell lines (DU145) showed constitutive activation of MAPK, while an androgen-dependent cell line (LNCaP) did not show MAPK activation. While MAPK were not activated in an androgen-sensitive Dunning G cell line, MAPK were activated in androgen-independent sublines (AT-3 and AT-6) derived from a G cell line. In addition, when SC115 cells were serially cultured without androgen, the cells 16-24 weeks after androgen removal showed MAPK activation. Furthermore, in subcloned cells, MAPK activation was observed even in the cells maintained for 9 weeks in medium without testosterone.Conclusions : The present findings suggest that constitutive activation of MAPK may be associated with the acquisition of hormone independence in prostate cancer and that clonal selection after androgen removal and hormone-independent growth through the MAPK signal transduction pathway could begin at a relatively early period in the individual cells.

Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling

“…Of relevance to the present study, a PDX model of PC devoid of AR signaling was shown to express high levels of FGF9, which promoted tumor growth, induced an osteoblastic tumor microenvironment, and responded to FGF-directed therapy (Li et al, 2008). MAPK signaling promotes poorly differentiated tumor growth in models of PC (Mulholland et al, 2012), and constitutive ERK1/2 activity is associated with castration resistance (Gioeli et al, 1999; Oka et al, 2005; Rodriguez-Berriguete et al, 2012). While there is evidence suggesting that MAPK can stimulate ligand-independent AR activity (Feldman and Feldman, 2001), FGF/MAPK signaling did not promote the re-expression of AR-regulated genes in our models and FGFR activity was inversely associated with the expression and activity of AR in CRPCs.…”

Coordinated steroid hormone-dependent and independent expression of multiple kallikreins in breast cancer cell lines

“…Using RAS effector-loop gain-of-function RAS mutant stable cell lines, it has been shown that constitutive MEK activation can hyper-induce PSA protein expression in LNCaP cells under normal levels of androgen [47,48]. Constitutive MEK activity was also correlated with the switch of prostate cancer cells lines from an androgen-dependent to an androgenindependent state [39,48].…”

“…The switch form hormone-dependent kallikrein gene expression to hormone-independent expression has been observed clinically for PSA (hK3) in prostate cancer. The conversion from hormone-dependent to hormone-independent expression has been correlated to several mutations including constitutive MEK-ERK activity and loss of the tumor suppressor protein phosphatase and tensin homologue deleted from chromosome 10 (PTEN) [39,40].…”

The PPAR Gamma Agonist Troglitazone Regulates Erk 1/2 Phosphorylation via a PPARγ-Independent, MEK-Dependent Pathway in Human Prostate Cancer Cells

“…Gioeli et al demonstrated that the amount of active phosphorylated Erk 1 and Erk 2 increases with increasing grade and stage of human prostate cancer [27]. Higher levels of activated Erk are also present in the more aggressive androgen-independent prostate cancer cells [28]. TZDs have been reported to regulate Erk activation in normal epithelium and cancer cells.…”