Regulation of Erk1/2 activation by osteopontin in PC3 human prostate cancer cells

Abstract

BackgroundOsteopontin (OPN) has been shown to play many roles in the progression of cancer. We have recently demonstrated the activation of Akt by OPN. Integrin-linked kinase and PI3-kinase are integral proteins in OPN/AKT pathway in PC3 cells. To investigate the role of the extracellular receptors in OPN signaling, we have examined the spatio-temporal regulation of CD44 and integrin αvβ3 receptor in OPN-induced Akt activation in PC3 cells.ResultsHere, our studies demonstrate that OPN can activate Akt either through the αVβ3 integrin or the CD44 cell surface receptor. Members of the Mitogen Activated Protein Kinase (MAPK) family have been shown to be up-regulated in a variety of human cancers and have been implicated in the metastatic behavior. Our studies have demonstrated an increase in the phosphorylation of c-Raf at Ser259 and Ser338 in PC3 cells over-expressing OPN. This increase matches up with the Erk1/2 phosphorylation at Thr202/204 and activation. However, the inhibition of Akt activity augments the phosphorylation state of ERK1/2 to two to three fold with a concomitant reduction in the phosphorylation state of c-Raf at Ser259.ConclusionsRegulation c-Raf phosphorylation at Ser259 has a role in the anti-apoptotic pathways mediated by Akt or Raf/MEK/ERK proteins. OPN may have dual effects in the activation of Erk1/2. We propose this based on the observations that while OPN activates c-Raf and Erk1/2; it also acts to inhibit c-Raf and Erk1/2 activation through Akt pathway. Our observations suggest that the activation of c-Raf-ERK cascade may promote cell cycle arrest in prostate cancer cells and OPN signaling has a role in the anti-apoptotic mechanism.

Protein Expression Analysis in Hematopoietic Stem Cells during Osteopontin-Induced Differentiation of Natural Killer Cells

“…Several receptors for osteopontin have been identifi ed in several cell types for a variety of physiological mechanisms, such as proliferation, differentiation and chemotaxis. For example, αXβ2 integrin functions as an OPN receptor for chemotaxis in monocytes (Schack et al, 2009), while OPN mediates metastasis via integrin αVβ3 and CD44 in tumor cells (Robertson et al, 2010). In this study, we found that expression of integrin α9 is notably increased in HSC by treatment of OPN.…”

Effects of Thymoquinone on IL-6 Gene Expression and Some Cellular Signaling Pathways in Prostate Cancer PC3 Cells

“…Therefore in the current study, another possible mechanism for antiproliferative effects of TQ on PC3 cells, at least in part, can be applied by reducing pAKT signaling pathway. Also, the ERK1/2 MAPK pathway (depending on the individual ligand, cell surface receptor, and cell type) is involved in the invasive, proliferation, differentiation, survival, metastatic, apoptosis, and development of several cancers through the phosphorylation of both cytoplasmic and nuclear targets including phosphatases, transcriptional factors, and cytoskeletal proteins (36,37). TQ can prevent proliferation and angiogenesis by suppressing ERK and AKT phosphorylation in human umbilical vein endothelial cells (HUVECs).…”

GD2 ganglioside specific antibody treatment downregulates PI3K/Akt/mTOR signaling network in human neuroblastoma cell lines

“…used in the study, the phosphatase is still active. Additionally, we have shown that c-Raf, a member of MAPKKKs (32), is slightly dephosphorylated at Ser259 (an inhibitory site) in the IMR-32 cells (Fig. 3C).…”

“…3C). The reduction of the phosphorylation state of c-Raf at Ser259 is following the inhibition of Akt in PC3 cells (a human prostatic adenocarcinoma cell line) (32).…”