MAP Kinases and Prostate Cancer

Rodríguez-Berriguete, Gonzalo; Fraile, Benito; Martínez-Onsurbe, Pilar; Olmedilla, Gabriel; Paniagua, Ricardo; Royuela, Mar

doi:10.1155/2012/169170

Cited by 105 publications

(65 citation statements)

References 118 publications

(141 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Of relevance to the present study, a PDX model of PC devoid of AR signaling was shown to express high levels of FGF9, which promoted tumor growth, induced an osteoblastic tumor microenvironment, and responded to FGF-directed therapy (Li et al, 2008). MAPK signaling promotes poorly differentiated tumor growth in models of PC (Mulholland et al, 2012), and constitutive ERK1/2 activity is associated with castration resistance (Gioeli et al, 1999; Oka et al, 2005; Rodriguez-Berriguete et al, 2012). While there is evidence suggesting that MAPK can stimulate ligand-independent AR activity (Feldman and Feldman, 2001), FGF/MAPK signaling did not promote the re-expression of AR-regulated genes in our models and FGFR activity was inversely associated with the expression and activity of AR in CRPCs.…”

Section: Discussionmentioning

confidence: 99%

Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling

et al. 2017

View full text Add to dashboard Cite

SUMMARY Androgen receptor (AR) signaling is a distinctive feature of prostate carcinoma (PC) and represents the major therapeutic target for treating metastatic prostate cancer (mPC). Though highly effective, AR antagonism can produce tumors that bypass a functional requirement for AR, often through neuroendocrine (NE) transdifferentiation. Through the molecular assessment of mPCs over two decades, we find a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype. These “double-negative” PCs are notable for elevated FGF and MAPK pathway activity, which can bypass AR dependence. Pharmacological inhibitors of MAPK or FGFR repressed the growth of double-negative PCs in vitro and in vivo. Our results indicate that FGF/MAPK blockade may be particularly efficacious against mPCs with an AR-null phenotype.

show abstract

Section: Discussionmentioning

confidence: 99%

Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling

et al. 2017

View full text Add to dashboard Cite

show abstract

“…However, generally, it appears that many if not most TKIs inhibit signaling downstream of growth factor receptors mediated by the PI3K-AKT and Ras-Raf-MEK-ERK pathways [15,16]. Activation of both the ERK and AKT pathways are a frequent event in prostate cancers and a strong association between the expression of these kinases and poor prognosis is often observed [17,18]. Thus, we tested whether sunitinib suppressed p-AKT and/or p-ERK, 2 appropriate downstream elements of the signaling pathways under investigation.…”

Section: Discussionmentioning

confidence: 99%

Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer

et al. 2012

View full text Add to dashboard Cite

BackgroundMany prostate cancers demonstrate an increased expression of growth factor receptors such as vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) which have been correlated with increased resistance to radiotherapy and poor prognosis in other tumors. Therefore, response to radiation could potentially be improved by using inhibitors of these abnormally activated pathways. We have investigated the radiosensitizing effects of sunitinib, a potent, multi-tyrosine kinase inhibitor of the VEGFR and PDGFR receptors, on human prostate cancer cells.MethodsThe radiosensitizing effects of sunitinib were assessed on human prostate cancer cell lines DU145, PC3 and LNCaP by clonogenic assay. Sunitinib’s ability to inhibit the activities of its key targets was determined by immunoblot analysis. The radiosensitizing effects of sunitinib in vivo were tested on human tumor xenografts growing in nude mice where response was assessed by tumor growth delay.ResultsClonogenic survival curve assays for both DU145 and PC3 cells showed that the surviving fraction at 2 Gy was reduced from 0.70 and 0.52 in controls to 0.44 and 0.38, respectively, by a 24 hr pretreatment with 100 nM sunitinib. LNCaP cells were not radiosensitized by sunitinib. Dose dependent decreases in VEGFR and PDGFR activation were also observed following sunitinib in both DU145 and PC3 cells. We assessed the ability of sunitinib to radiosensitize PC3 xenograft tumors growing in the hind limb of nude mice. Sunitinib given concurrently with radiation did not prolong tumor growth delay. However, when animals were treated with sunitinib commencing the day after fractionated radiation was complete, tumor growth delay was enhanced compared to radiation alone.ConclusionsWe conclude, based on the in vivo results, that sunitinib and radiation do not interact directly to radiosensitize the PC3 tumor cells in vivo as they did in vitro. The fact that tumor growth delay was enhanced when sunitinib was given after radiotherapy was completed suggests that sunitinib may be acting on the irradiated tumor stroma and suppressing its ability to sustain regrowth of the irradiated tumor. Based on these preclinical findings, we suggest that the combination of sunitinib and radiation for the treatment of prostate cancer deserves further development.

show abstract

“…The 3 main members that integrate the MAPK family in mammalian cells are stress-activated protein kinase c-Jun NH2-terminal kinase (JNK), stress-activated protein kinase 2 (SAPK2, p38) and the extracellular signal-regulated protein kinases (ERK1/2, p44/p42) (33). MAPK p38 has been shown to be activated by cellular stress, UV radiation, growth factor withdrawal and pro-inflammatory cytokines (34).…”

Section: Discussionmentioning

confidence: 99%

Oridonin enhances antitumor activity of gemcitabine in pancreatic cancer through MAPK-p38 signaling pathway

Luo

Chen

et al. 2012

International Journal of Oncology

View full text Add to dashboard Cite

Gemcitabine is currently the best treatment available for pancreatic cancer (PaCa); however, patients with the disease develop resistance to the drug over time. Agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are required for the treatment of PaCa. Oridonin is one such agent which is safe and multitargeted, and has been linked with the suppression of survival, proliferation, invasion and angiogenesis of cancer. In this study, we investigated whether oridonin could sensitize PaCa to gemcitabine in vitro and in vivo. In vitro, oridonin inhibited the proliferation of the PaCa cell line, BxPC-3, potentiated the apoptosis induced by gemcitabine, induced G1 cell cycle arrest and activated p38 and p53; these results were significant when oridonin was combined with gemcitabine. In vivo, we found that oridonin significantly suppressed tumor growth and this effect was further enhanced by gemcitabine (P<0.05). Tumors from nude mice injected with BxPC-3 PaCa cells and treated with a combination of oridonin and gemcitabine showed a significant upregulation in p38 and p53 activation (P<0.05 vs. control, P<0.05 vs. gemcitabine or oridonin alone). Taken together, our results demonstrate that oridonin can potentiate the effects of gemcitabine in PaCa through the mitogen-activated protein kinase (MAPK)-p38 signaling pathway, which is dependent on p53 activation.

show abstract

MAP Kinases and Prostate Cancer

Cited by 105 publications

References 118 publications

Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling

Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling

Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer

Oridonin enhances antitumor activity of gemcitabine in pancreatic cancer through MAPK-p38 signaling pathway

Contact Info

Product

Resources

About