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

Abstract

Purpose: Y-box-binding protein-1 (YB-1) is known to conduct various functions related to cell proliferation, anti-apoptosis, epithelial-mesenchymal transition, and castration resistance in prostate cancer. However, it is still unknown how YB-1 affects cancer biology, especially its correlations with the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, we aimed to examine the interaction between YB-1 and the MAPK pathway in prostate cancer.Experimental Design: Quantitative real-time PCR, Western blotting, and co-immunoprecipitation assay were conducted in prostate cancer cells. YB-1, phosphorylated YB-1 (p-YB-1), and ERK2 protein expressions in 165 clinical specimens of prostate cancer were investigated by immunohistochemistry. YB-1, p-YB-1, and ERK2 nuclear expressions were compared with clinicopathologic characteristics and patient prognoses.Results: EGF upregulated p-YB-1, whereas MEK inhibitor (U0126, PD98059) decreased p-YB-1. Inversely, silencing of YB-1 using siRNA decreased the expression of ERK2 and phosphorylated MEK, ERK1/2, and RSK. Furthermore, YB-1 interacted with ERK2 and Raf-1 and regulated their expressions, through the proteasomal pathway. Immunohistochemical staining showed a significant correlation among the nuclear expressions of YB-1, p-YB-1, and ERK2. The Cox proportional hazards model revealed that high ERK2 expression was an independent prognostic factor [HR, 7.947; 95% confidence interval (CI), 3.527-20.508; P < 0.0001].Conclusion: We revealed the functional relationship between YB-1 and MAPK signaling and its biochemical relevance to the progression of prostate cancer. In addition, ERK2 expression was an independent prognostic factor. These findings suggest that both the ERK pathway and YB-1 may be promising molecular targets for prostate cancer diagnosis and therapeutics.

The RNA-Binding Protein PCBP1 Functions as a Tumor Suppressor in Prostate Cancer by Inhibiting Mitogen Activated Protein Kinase 1

“…Both p38 MAPK and MAPK1 has been shown to regulate E-cadherin-mediated phenotypic switching in prostate cancer [12]. ERK2 was shown as an independent prognostic marker for prostate cancer [13]. In fact, ERK2 along with the Y-box binding protein was shown to promote prostate cancer progression [13].…”

Knockdown of Y-box-binding protein-1 inhibits the malignant progression of HT-29 colorectal adenocarcinoma cells by reversing epithelial-mesenchymal transition

“…In prostate cancer, research found that knockdown of YB-1 caused a 50% reduction in cell invasion, and further investigation suggested that YB-1 regulated EMT by mammalian target of rapamycin and mitogen-activated protein kinase signaling (9,27). In melanoma, the stimulating function of YB-1 in proliferation, invasion, apoptosis resistance and chemoresistance and the regulation of YB-1 in EMT-related signaling pathways have been widely proved (29,30).…”

“…Recent studies have regarded YB-1 as an oncoprotein due to its involvement in uncontrolled proliferation (2), apoptosis resistance (3), sustained angiogenesis (4), invasion and metastasis (5). Furthermore, YB-1 has been associated with chemotherapeutic resistance (6) and high YB-1 expression is closely linked to the poor clinical outcome in various types of cancer, including gastric (7), ovarian (8) and prostate (9). Other studies have suggested that the carcinogenic effect of YB-1 may be associated with epithelial-to-mesenchymal transition (EMT) (10,11).…”

Two p90 Ribosomal S6 Kinase Isoforms Are Involved in the Regulation of Mitotic and Meiotic Arrest in Artemia

“…The ribosomal S6 kinase (RSK) 2 family comprises a group of ERK/MAPK effectors that regulate diverse cellular functions by phosphorylating nuclear and cytoplasmic targets. Hyperactive RSK signaling regulates cell division in several types of cancer, including breast, prostate, and lung (1)(2)(3).…”

“…Hyperactive RSK signaling regulates cell division in several types of cancer, including breast, prostate, and lung (1)(2)(3). The RSK inhibitor SL-0101 arrests MCF-7 cells (a breast cancer cell line) in the G 1 phase, and thereby inhibits their proliferation (1).…”