Deregulated Akt3 Activity Promotes Development of Malignant Melanoma

Stahl, Jill M.; Sharma, Arti; Cheung, Mitchell; Zimmerman, Melissa; Cheng, Jin Q.; Bosenberg, Marcus W.; Kester, Mark; Sandirasegarane, Lakshman; Robertson, Gavin P.

doi:10.1158/0008-5472.can-04-1399

Cited by 530 publications

(658 citation statements)

References 32 publications

Supporting

Mentioning

629

Contrasting

Unclassified

Order By: Relevance

“…Although experiments in fibroblasts have implicated a role for PI-3 kinase/Akt signaling in the regulation of p27 Kip1 (Mirza et al, 2004), we have not observed alterations in p27 Kip1 levels upon treatment with the PI-3 kinase inhibitor, LY294002, in melanoma cell lines (data not shown). Nevertheless, the role of PI-3 kinase/Akt signaling in melanoma cell cycle events warrants further investigation as this pathway is frequently altered (Stahl et al, 2004). p27 Kip1 levels in melanoma cells are also regulated by the proteasome.…”

Section: Discussionmentioning

confidence: 99%

Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells

Bhatt

Spofford

et al. 2006

Oncogene

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells

Bhatt

Spofford

et al. 2006

Oncogene

View full text Add to dashboard Cite

“…We predicted that IGF1R knock-down was inhibiting signaling via other pathways including PI3K-Akt that have a major influence on survival (Peruzzi et al, 1999). Indeed blockade of the PI3K-Akt pathway was shown to be capable of inducing apoptosis and inhibiting melanoma tumor development (Stahl et al, 2004). In CHL-1 cells transfected with empty vector or WT B-RAF, we observed a decrease in Akt phosphorylation two days post-transfection with IGF1R siRNA (Figure 4a).…”

Section: Igf1r Targeting In V600e B-raf Melanomamentioning

confidence: 90%

Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs

2006

View full text Add to dashboard Cite

The type 1 insulin-like growth factor receptor (IGF1R) is overexpressed by malignant melanomas compared with benign naevi, and mediates proliferation, motility and protection from apoptosis. However, the utility of IGF1R targeting as anti-cancer therapy may be limited by activating mutations in downstream signaling intermediates. We previously showed that IGF1R knockdown blocked survival of prostate cancer cells in which Akt activation was deregulated by PTEN loss. The current study investigated effects of IGF1R targeting in cells harboring activating RAS-RAF mutations, found in 70-80% of human melanomas. We assembled a panel of eight human melanoma cell lines: two expressing wild-type (WT) B-RAF and N-RAS, two with activating N-RAS mutations and four harboring V600E B-RAF. We also generated isogenic cell populations overexpressing WT or V600E B-RAF. Cells expressing V600E B-RAF were relatively resistant to apoptosis. However, IGF1R gene silencing was capable of inducing significant inhibition of survival, enhancement of apoptosis, and Btwo-fold sensitization to cisplatin and temozolomide. These effects were independent of mutation status and were associated with reduced activation of Akt and also, unexpectedly, of ERKs. These results support development of IGF1R targeting as therapy for melanoma, regardless of the presence of activating mutations in the RAS-RAF pathway.

show abstract

“…In addition, DNA copy gain involving the AKT3 locus has recently been described in melanoma, and selective AKT3 activation may characterize 40%-60% of sporadic tumors (Stahl et al 2004). However, the complexity of this signaling cascade has not been fully understood.…”

Section: Pten Negative Regulator Of Phosphatidylinositol 3-kinase (Pmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

View full text Add to dashboard Cite

Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

show abstract

Deregulated Akt3 Activity Promotes Development of Malignant Melanoma

Cited by 530 publications

References 32 publications

Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells

Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells

Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs

Malignant melanoma: genetics and therapeutics in the genomic era

Contact Info

Product

Resources

About