ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK)

Aguirre‐Ghiso, Julio A.; Estrada, Yeriel; Liu, D.; Ossowski, Liliana

doi:10.1016/j.urolonc.2003.12.012

Cited by 343 publications

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“…20 Together these findings suggest that p38 does not play a major role in the development or progression of melanocytic tumors and that the observed activation is rather an effector of other signaling pathways. In support of this, Aguirre-Ghiso et al 11 suggested that the p38 pathway may be altered or dysfunctional in melanomas.…”

Section: Discussionmentioning

confidence: 91%

“…11,[27][28][29][30][31][32] We observed a strong significant positive association between the activation status of cytoplasmic JNK, p38, and ERK1/2 in superficial spreading melanomas as well as an association between activation of Akt and p38 in the cytoplasm. In a study by Pedram et al 32 expression of vascular endothelial growth factor was shown to induce a positive ERK1/2-JNK crosstalk in endothelial cells.…”

Section: Discussionmentioning

confidence: 95%

“…Moreover, our data are not in agreement with studies showing a negative cross-talk mechanism between p38 and ERK1/2 in several tissues. 11,[27][28][29] Common for these studies is the observation that inhibiting one pathway induces a robust increase in activation of the other and vice versa. This again demonstrates the complexity of signaling in different environments.…”

Section: Discussionmentioning

confidence: 99%

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Activation of c-jun N-terminal kinase is associated with cell proliferation and shorter relapse-free period in superficial spreading malignant melanoma

2006

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Signaling pathways regulating cell proliferation and survival have become attractive targets for anticancer strategies. In the present study, we analyzed by immunohistochemistry, a panel of benign nevi, superficial spreading and nodular primary melanomas and metastases for expression of activated p38/mitogen-activated protein kinase (p-p38) and c-jun N-terminal kinase (JNK) (p-JNK) and correlated the findings with known prognostic variables. Twenty-five and 35% of the primaries and 9 and 25% of the metastases expressed variable levels of p-p38 and p-JNK, respectively. In benign nevi, 73.5% expressed p-JNK and 7% expressed p-p38. For patients with superficial spreading melanomas, high level of cytoplasmic p-JNK was associated with thicker tumors (P ¼ 0.017) and shorter disease-free survival (P ¼ 0.003) as well as with markers of cell proliferation (cyclin A (P ¼ 0.017) and p21 (P ¼ 0.021)). In nodular melanomas, nuclear p-p38 was associated with Ki-67 (P ¼ 0.012), but neither cytoplasmic nor nuclear localized p-p38 was associated with disease outcome. Of note, in superficial spreading melanomas, a positive correlation between cytoplasmic p-JNK and cytoplasmic p-extracellular signal-regulated kinase ERK1/2 (P ¼ 0.005) and p-p38 (P ¼ 0.003) was observed. Likewise, p-p38 in cytoplasm was positively associated with cytoplasmic p-ERK1/2 (Po0.0005) and p-Akt (P ¼ 0.047). In contrast, except for a positive correlation between nuclear p-p38 and membranous p-TrkA (P ¼ 0.02), no correlation between the activation status of the different signaling pathways was observed in nodular melanomas. In conclusion, our results suggest that in benign nevi activated JNK may have a role in restricting uncontrolled cell proliferation or survival. However, during tumor progression, activation of JNK is associated with cell proliferation and shorter relapse-free period for patients with superficial spreading melanomas, suggesting that the JNK activation status could be a marker for clinical outcome in at least a subgroup of malignant melanoma. In contrast, activation of p38 seems to play a less important role in development and progression of malignant melanomas.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Activation of c-jun N-terminal kinase is associated with cell proliferation and shorter relapse-free period in superficial spreading malignant melanoma

2006

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“…Our present work suggests that the suppression of migration and invasion by Pdcd4 is, at least in part, brought about by a downregulation of the urokinase receptor (u-PAR), which, together with its binding enzyme u-PA and its specific inhibitor PAI-1, has been well established as a proteolytic system promoting invasion/metastasis and a poor clinical prognosis in diverse cancers (Duffy, 1987;Blasi, 1993;Heiss et al, 1996;Muehlenweg et al, 2001). Although it is well established that u-PAR is regulated by many growth factors, oncogenes (Boyd and Brattain, 1989;Lengyel et al, 1996;Allgayer et al, 1999a-c) and signaling cascades promoting proliferation/progression (AguirreGhiso et al, 2001;Aguirre-Ghiso et al, 2003;Ahmed et al, 2003), no tumor suppressor gene has been identified so far regulating u-PAR gene expression (Fuchs and Allgayer, 2003). According to previous studies, the regulation of u-PAR gene expression has largely been observed at the transcriptional level (Wang et al, 1994;Wagner et al, 1995;Lengyel et al, 1996), and correspondingly, we showed that Pdcd4 reduces u-PAR promoter activity, and that siPdcd4 induces u-PAR mRNA, in our cell lines studied, suggesting transcriptional regulation.…”

Section: Pdcd4 Regulates Invasion and U-par Expressionmentioning

confidence: 99%

Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors

et al. 2007

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“…(76) Recent findings indicated that androgen-independent proliferation of prostate cancer cells may be, at least in part, regulated via p38 activation. (77) The molecular mechanism of AR-MAPK pathway interactions may be a combination of MAPK phosphorylation of AR to sensitize it to 5a-dihydrotestosterone (DHT), facilitation of AR entry into the nucleus, and MAPK phosphorylation of an AR coactivator, such as SRC-1, to increase AR transcriptional activity (e.g.…”

Section: Mapk Signalingmentioning

confidence: 99%

Androgen signaling and its interactions with other signaling pathways in prostate cancer

2007

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SummaryProstate cancer is the most frequently diagnosed nonskin cancer and the third leading cause of cancer mortality in men. In the initial stages, prostate cancer is dependent on androgens for growth, which is the basis for androgen ablation therapy. However, in most cases, prostate cancer progresses to a hormone refractory phenotype for which there is no effective therapy available at present. The androgen receptor (AR) is required for prostate cancer growth in all stages, including the relapsed, ''androgen-independent'' tumors in the presence of very low levels of androgens. This review focuses on AR function and AR-target genes and summarizes the major signaling pathways implicated in prostate cancer progression, their crosstalk with each other and with AR signaling. This complex network of interactions is providing a deeper insight into prostate carcinogenesis and may form the basis for novel diagnostic and therapeutic strategies. IntroductionProstate adenocarcinoma is the most frequently diagnosed non-cutaneous male malignancy and the third leading cause of cancer-related death in men in most western industrialized countries. (1) It is estimated that around 660,000 men worldwide will be diagnosed with prostate cancer and 250,000 men will die from it in 2010; thus, it will remain a major health problem in the future. (1) It was more than 60 years ago that the important role of male sex hormones (androgens) for the development and growth of prostate cancer was demonstrated. (2) Accordingly, androgen ablation therapy has been the main line of therapy for prostate cancer. Therefore, much of the focus in prostate cancer research to date has naturally been on androgens, how to decrease the androgens in the circulation and how to inhibit the androgen receptor (AR).In addition to AR signaling, it has now become evident that other signaling pathways, as well as non-genomic and genomic alterations, are involved in prostate cancer development and progression. Furthermore, recent studies indicated that signaling through AR has a critical role even after androgen ablation and disease progression (for review see Ref.3). In the following sections, we give an overview of androgen signaling in prostate cancer, with a special focus on recent findings about AR function and AR target genes. We then review the involvement of other central signaling pathways in prostate cancer, with a special focus on their cross-talk with the AR signaling pathway. Clinical implications of these findings and potential directions for future research are also outlined.

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ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK)

Cited by 343 publications

References 0 publications

Activation of c-jun N-terminal kinase is associated with cell proliferation and shorter relapse-free period in superficial spreading malignant melanoma

Activation of c-jun N-terminal kinase is associated with cell proliferation and shorter relapse-free period in superficial spreading malignant melanoma

Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors

Androgen signaling and its interactions with other signaling pathways in prostate cancer

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