EP4 mediates PGE2 dependent cell survival through the PI3 kinase/AKT pathway

George, Robert; Sturmoski, Mark; Anant, Shrikant; Houchen, Courtney W.

doi:10.1016/j.prostaglandins.2006.10.005

Cited by 65 publications

(62 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition, EP4 activation can also stimulate PI3K/AkT pathway, 29 to promote PGE2-dependent cell survival. 40 In this study, residual tumors in mice treated with indomethacin, celecoxib as well as the EP4 antagonist ONO-AE3-208 showed a parallel reduction of AkT phosphorylation ¼ 12)±s.e., *Po0.05. ; **Po0.005 comparing the two groups.…”

Section: Therapy With Cox-1/2 Inhibitor Cox-2 Inhibitor or Ep4 Antagmentioning

confidence: 61%

“…Although an activation of both EP2 and EP4 receptors stimulate the cAMP pathway, EP4 activation also stimulates PI3K/AkT pathway to promote tumor growth/survival. 29,40 For this reason, we tested whether the cyto-reductive effects of indomethacin, celecoxib and EP4 antagonist therapies, were all associated with reduction of EP4 activity and thereby a reduction of AkT phosphorylation in the tumors. Western blot data in Figure 6 and apoptotic/ proliferative cell ratios in Figure 7 confirm this contention.…”

Section: Therapy With Cox-1/2 Inhibitor Cox-2 Inhibitor or Ep4 Antagmentioning

confidence: 99%

“…As EP4 is the only EP receptor known to be linked with AkT activation, we believe that a blockade in EP4 signaling resulted from all the afore-mentioned therapies. The cyto-reductive effects of these therapies on the primary tumor can be attributed to both direct and indirect effects of the drugs on tumor cells, mediated by EP4 receptor inactivation: the direct effects, by blocking PGE2-dependent tumor cell survival; 40 and the indirect effects because of a reduction in blood supply required for tumor cell oxygenation, proliferation and survival. This contention is supported by the findings that a reduction in tumor growth was preceded by a reduction in angiogenesis.…”

Section: Therapy With Cox-1/2 Inhibitor Cox-2 Inhibitor or Ep4 Antagmentioning

confidence: 99%

See 2 more Smart Citations

Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model

Xin

Majumder

Girish

et al. 2012

Laboratory Investigation

112

160

View full text Add to dashboard Cite

We reported that cyclo-oxygenase (COX)-2 expression in human breast cancer stimulated cancer cell migration and invasiveness, production of vascular endothelial growth factor (VEGF)-C and lymphangiogenesis in situ, largely from endogenous PGE2-mediated stimulation of prostaglandin E (EP)1 and EP4 receptors, presenting them as candidate therapeutic targets against lymphatic metastasis. As human breast cancer xenografts in immuno-compromised mice have limitations for preclinical testing, we developed a syngeneic murine breast cancer model of spontaneous lymphatic metastasis mimicking human and applied it for mechanistic and therapeutic studies. We tested the roles of COX-2 and EP receptors in VEGF-C and -D production by a highly metastatic COX-2 expressing murine breast cancer cell line C3L5. These cells expressed all EP receptors and produced VEGF-C and -D, both inhibited with COX-2 inhibitors or EP4 (but not EP1, EP2 or EP3) antagonists. C3H/HeJ mice, when implanted SC in both inguinal regions with C3L5 cells suspended in growth factor-reduced Matrigel, exhibited rapid tumor growth, tumor-associated angiogenesis and lymphangiogenesis (respectively measured with CD31 and LYVE-1 immunostaining), metastasis to the inguinal and axillary lymph nodes and the lungs. Chronic oral administration of COX-1/COX-2 inhibitor indomethacin, COX-2 inhibitor celecoxib and an EP4 antagonist ONO-AE3-208, but not an EP1 antagonist ONO-8713 at nontoxic doses markedly reduced tumor growth, lymphangiogenesis, angiogenesis, and metastasis to lymph nodes and lungs. Residual tumors in responding mice revealed reduced VEGF-C and -D proteins, AkT phosphorylation and increased apoptotic/proliferative cell ratios consistent with blockade of EP4 signaling. We suggest that EP4 antagonists deserve clinical testing for chemo-intervention of lymphatic metastasis in human breast cancer.

show abstract

Section: Therapy With Cox-1/2 Inhibitor Cox-2 Inhibitor or Ep4 Antagmentioning

confidence: 61%

Section: Therapy With Cox-1/2 Inhibitor Cox-2 Inhibitor or Ep4 Antagmentioning

confidence: 99%

Section: Therapy With Cox-1/2 Inhibitor Cox-2 Inhibitor or Ep4 Antagmentioning

confidence: 99%

See 1 more Smart Citation

Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model

Xin

Majumder

Girish

et al. 2012

Laboratory Investigation

112

160

View full text Add to dashboard Cite

show abstract

“…Because PGE 2 is reported to exert its antiapoptotic effect through cAMP/PKA or PI3K/Akt signaling pathways (39,(41)(42)(43), these kinases may be responsible for the protective effect observed in our study. Given the fact that neither UUO injury nor the Sirt1 activator induces COX2 expression in renal medullary collecting duct cells in vivo, the Sirt1-dependent COX2 induction and PGE 2 production may be a RMIC-specific protective mechanism.…”

Section: Figurementioning

confidence: 65%

Sirt1 activation protects the mouse renal medulla from oxidative injury

He¹,

Wang²,

Zhang³

et al. 2010

J. Clin. Invest.

277

247

View full text Add to dashboard Cite

Sirtuin 1 (Sirt1) is a NAD + -dependent deacetylase that exerts many of the pleiotropic effects of oxidative metabolism. Due to local hypoxia and hypertonicity, the renal medulla is subject to extreme oxidative stress. Here, we set out to investigate the role of Sirt1 in the kidney. Our initial analysis indicated that it was abundantly expressed in mouse renal medullary interstitial cells in vivo. Knocking down Sirt1 expression in primary mouse renal medullary interstitial cells substantially reduced cellular resistance to oxidative stress, while pharmacologic Sirt1 activation using either resveratrol or SRT2183 improved cell survival in response to oxidative stress. The unilateral ureteral obstruction (UUO) model of kidney injury induced markedly more renal apoptosis and fibrosis in Sirt1 +/-mice than in wild-type controls, while pharmacologic Sirt1 activation substantially attenuated apoptosis and fibrosis in wild-type mice. Moreover, Sirt1 deficiency attenuated oxidative stress-induced COX2 expression in cultured mouse renal medullary interstitial cells, and Sirt1 +/-mice displayed reduced UUO-induced COX2 expression in vivo. Conversely, Sirt1 activation increased renal medullary interstitial cell COX2 expression both in vitro and in vivo. Furthermore, exogenous PGE 2 markedly reduced apoptosis in Sirt1-deficient renal medullary interstitial cells following oxidative stress. Taken together, these results identify Sirt1 as an important protective factor for mouse renal medullary interstitial cells following oxidative stress and suggest that the protective function of Sirt1 is partly attributable to its regulation of COX2 induction. We therefore suggest that Sirt1 provides a potential therapeutic target to minimize renal medullary cell damage following oxidative stress.

show abstract

“…PGE 2 is one of the stimulators of osteoclastogenesis, with induction of RANKL in osteoblasts (17,18). Moreover, PGE 2 was reported to abolish apoptosis in some cancer cells by upregulating antiapoptotic proteins and enhancing cell survival pathways (35,36). However, the possibility that secreted FuEP2/Ex2 may directly induce apoptosis of cancer cells can be excluded, because the growth rate of PC3-FuEP2/Ex2 cells in vitro was almost the same as that of the parental cells.…”

Section: Discussionmentioning

confidence: 99%

Soluble EP2 neutralizes prostaglandin E2–induced cell signaling and inhibits osteolytic tumor growth

Takahashi

Uehara

Bando

et al. 2008

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Prostaglandin E 2 (PGE 2 ) plays a key role in osteolytic bone metastasis as well as roles in inflammation, cell growth, and tumor development. PGE 2 exerts its effects by binding and activating E-prostanoid receptor (EP). In this study, we propose a new approach for blocking EP-mediated cell signaling using a soluble chimeric EP2 fragment. Mammalian expression vectors encoding several human EP2 cDNAs were introduced into 293 cells and the culture medium was tested for their function as a decoy receptor for PGE 2 . PGE 2 binding assays revealed that culture medium containing the second extracellular region of EP2 (FuEP2/Ex2) had binding activity. FuEP2/Ex2 neutralized PGE 2 -induced cyclic AMP production, cyclic AMP -responsive element binding protein phosphorylation, and subsequent induction of cyclooxygenase-2, interleukin (IL)-1B, and IL-6 mRNAs. In human osteoblasts, this culture medium neutralized the induction of receptor activator of nuclear factor-KB ligand mRNA. A stable transfectant expressing FuEP2/Ex2 was established from human prostate cancer PC-3 cells (PC3-FuEP2/Ex2). PC3-FuEP2/Ex2 cells grew at similar rates to vector control cells under normal culture conditions, although PGE 2 -induced growth stimulation was suppressed. Intraosseous injection of PC3-FuEP2/Ex2 cells into the tibia of athymic nude mice revealed that the degrees of tumor growth and osteolysis were decreased compared with control cellinjected mice, with decreased osteoclasts and increased apoptotic cells. Furthermore, the cyclooxygenase-2, IL-1B, and IL-6 mRNA levels were reduced in the tumor lesions. These data suggest that FuEP2/Ex2 is useful for treating osteolytic bone metastasis and cancers that depend on EP signaling for their growth and development.

show abstract

EP4 mediates PGE2 dependent cell survival through the PI3 kinase/AKT pathway

Cited by 65 publications

References 32 publications

Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model

Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model

Sirt1 activation protects the mouse renal medulla from oxidative injury

Soluble EP2 neutralizes prostaglandin E2–induced cell signaling and inhibits osteolytic tumor growth

Contact Info

Product

Resources

About