Upregulation of MAPK pathway is associated with survival in castrate-resistant prostate cancer

Abstract

Background:Recent evidence has implicated the MAP kinase (MAPK) pathway with the development of castrate-resistant prostate cancer (CRPC). We have previously reported gene amplification of critical members of this pathway with the development of castrate-resistant disease. In addition, we have shown that rising Raf-1 expression, with the development of CRPC, influences time to biochemical relapse. We therefore sought to further analyse the role of both Raf-1 and its downstream target MAPK in the molecular pathogenesis of CRPC.Methods:Protein expression of Raf-1 and MAPK, including their activation status, was analysed using immunohistochemistry in a database of 65 paired tumour specimens obtained before and after the development of CRPC and correlated with other members of the pathway.Results:Patients whose nuclear expression of MAPK rose with the development of CRPC had a significantly shorter median time to death following biochemical relapse (1.40 vs 3.00 years, P=0.0255) as well as reduced disease-specific survival when compared with those whose expression fell or remained unchanged (1.16 vs 2.62 years, P=0.0005). Significant correlations were observed between protein expression of Raf-1 and MAPK with the type 1 receptor tyrosine kinases, Her2 and epidermal growth factor receptor, as well as the transcription factor AP-1 in CRPC tumours.Conclusion:We conclude that the Her2/Raf-1/MAPK/AP-1 axis may promote the development of CRPC, leading to early relapse, and reduced disease-specific survival. In addition, members of the pathway may act as novel therapeutic and/or diagnostic targets for prostate cancer.

Mutual Regulation between Raf/MEK/ERK Signaling and Y-Box–Binding Protein-1 Promotes Prostate Cancer Progression

“…In addition, the phosphorylated ERK levels have also been shown to be increased in prostate cancer, especially after ADT, and to be correlated with the Gleason score and tumor stage (48,49). Also, an increase in nuclear ERK has been correlated with poor survival (50). Similarly, in the present study, nuclear ERK2 expression was correlated with increased malignant potential of prostate cancer, such as advanced pathologic stage and higher PSA recurrence.…”

“…Similarly, ERK is well known to promote prostate cancer growth (52) and progression (53) as well as castration resistance (50,54). Inversely, inhibition of ERK signaling has been shown to exert therapeutic effects on prostate cancer (55).…”

Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling

“…The RAS/MAPK pathway is significantly elevated in both primary and metastatic prostate cancer, and its activation promotes aggressive tumor behavior, but there is no information about its implication in tumor initiation. 36,37 Although CHKB has been shown to be involved in carcinogenesis in different types of solid tumors, to our knowledge, it has not been studied in human prostate cancer. 38 Different metalloproteinases, including MMP13, which has previously been linked to prostate cancer, were also up-regulated in the ODC-overexpressing cells in our study.…”

Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer

“…Deregulation of these miRNAs may cause defects in cell cycle checkpoint control and further promote cell cycle progression by decreasing the expression levels of tumor suppressors PTEN, p21 and Rb1, which are commonly inactivated in PCa (reviewed by Lee et al, 2008). In addition, decreased expression of miR-27, miR-143 and miR-221/222 may promote increased expression of Notch1, MAPK kinases and c-KIT, which have been associated with epithelialmesenchymal transition, angiogenesis and metastasis in PCa (Paronetto et al, 2004;Bin Hafeez et al, 2009;Mukherjee et al, 2011).…”