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Inhibition of EP2/EP4 signaling abrogates IGF-1R-mediated cancer cell growth: involvement of protein kinase C-? activation.

ABSTRACT: Associations between growth factor receptor-mediated cell signaling and cancer cell growth have been previously characterized. Receptors for prostaglandin E2, such as EP2, and EP4, play roles in cancer growth, progression and invasion. Thus, we examined the interactions between EP2/EP4- and IGF-1R-mediated cellular signaling in human pancreatic cancer cells. Selective antagonists against EP2 and EP4 abrogated IGF-1-stimulated cell growth and suppressed MEK/ERK phosphorylation. In subsequent experiments, phospho-antibody arrays indicated increased phosphorylation levels of protein kinase C-? (PKC-?) at the Thr538 position following the inhibition of EP2/EP4-mediated signaling. Inhibition of PKC-? activity impaired cell viability compared with EP2/EP4-antagonized IGF-1-stimulated cells. PKC-? kinase MAP4K3, which plays a pivotal role in PKC-? activation, also affected growth signaling in the presence of EP2/EP4 antagonists. Administration of EP2 and EP4 antagonists significantly inhibited the growth of an orthotopic xenograft of IGF-1-secreting pancreatic cancer cells, with increased phospho-PKC-? and decreased phospho-ERK. Clinico-pathological analyses showed that 17.4% of surgical pancreatic cancer specimens were quadruple-positive for IGF-1R, EP2 (or EP4), MAP4K3, and PKC-?. These results indicate a novel signaling crosstalk between EP2/EP4 and IGF-1R in cancer cells, and suggest that the MAP4K3-PKC-? axis is central and could be exploited as a molecular target for cancer therapy.

SUBMITTER: Takahashi T

PROVIDER: S-EPMC4467118 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Inhibition of EP2/EP4 signaling abrogates IGF-1R-mediated cancer cell growth: involvement of protein kinase C-θ activation.

Takahashi Tetsuyuki T Uehara Hisanori H Ogawa Hirohisa H Umemoto Hitomi H Bando Yoshimi Y Izumi Keisuke K

Oncotarget 20150301 7

Associations between growth factor receptor-mediated cell signaling and cancer cell growth have been previously characterized. Receptors for prostaglandin E2, such as EP2, and EP4, play roles in cancer growth, progression and invasion. Thus, we examined the interactions between EP2/EP4- and IGF-1R-mediated cellular signaling in human pancreatic cancer cells. Selective antagonists against EP2 and EP4 abrogated IGF-1-stimulated cell growth and suppressed MEK/ERK phosphorylation. In subsequent expe ...[more]

PMID: 25638159

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Project description:Primary bone tumor, also known as osteosarcoma (OS), is the most common primary malignancy of bone in children and young adults. Current treatment protocols yield a 5-year survival rate of near 70% although approximately 80% of patients have metastatic disease at the time of diagnosis. However, long-term survival rates have remained virtually unchanged for nearly four decades, largely due to our limited understanding of the disease process. One major signaling pathway that has been implicated in human OS tumorigenesis is the insulin-like growth factor (IGF)/insulin-like growth factor-1 receptor (IGF1R) signaling axis. IGF1R is a heterotetrameric α2β2 receptor, in which the α subunits comprise the ligand binding site, whereas the β subunits are transmembrane proteins containing intracellular tyrosine kinase domains. Although numerous strategies have been devised to target IGF/IGF1R axis, most of them have failed in clinical trials due to the lack of specificity and/or limited efficacy. Here, we investigated whether a more effective and specific blockade of IGF1R activity in human OS cells can be accomplished by employing dominant-negative IGF1R (dnIGF1R) mutants. We engineered the recombinant adenoviruses expressing two IGF1R mutants derived from the α (aa 1-524) and β (aa 741-936) subunits, and found that either dnIGF1Rα and/or dnIGF1Rβ effectively inhibited cell migration, colony formation, and cell cycle progression of human OS cells, which could be reversed by exogenous IGF1. Furthermore, dnIGF1Rα and/or dnIGF1Rβ inhibited OS xenograft tumor growth in vivo, with the greatest inhibition of tumor growth shown by dnIGF1Rα. Mechanistically, the dnIGF1R mutants down-regulated the expression of PI3K/AKT and RAS/RAF/MAPK, BCL2, Cyclin D1 and most EMT regulators, while up-regulating pro-apoptotic genes in human OS cells. Collectively, these findings strongly suggest that the dnIGF1R mutants, especially dnIGF1Rα, may be further developed as novel anticancer agents that target IGF signaling axis with high specificity and efficacy.

Dataset Information

Inhibition of EP2/EP4 signaling abrogates IGF-1R-mediated cancer cell growth: involvement of protein kinase C-? activation.

Publications

Inhibition of EP2/EP4 signaling abrogates IGF-1R-mediated cancer cell growth: involvement of protein kinase C-θ activation.

Similar Datasets

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