Malignant Transformation of Melanocytes to Melanoma by Constitutive Activation of Mitogen-activated Protein Kinase Kinase (MAPKK) Signaling

Gunasekaran, Baskaran; Bai, Xianhe; Cohen, Cynthia; Zhong, Hua; Kilroy, Susan; Louis, Gwendolyn W.; Moses, Marsha A.; Arbiser, Jack L.

doi:10.1074/jbc.m212929200

Cited by 113 publications

(84 citation statements)

References 44 publications

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“…But within cancers, the over-activation of this MAPK pathway often results from mutations in the proto-oncogene Ras, or the activating mutation of B-Raf 204 . As discussed earlier, the MAPK pathway is observed to be hyperactivated in melanoma, but not in melanocytes 205 . The activation of ERK1/2 by oncogenic Ras or B-Raf contributes to the increased proliferation rate seen in tumours and as such is an attractive target for cancer therapies.…”

Section: The Mapk Pathwaymentioning

confidence: 59%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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Section: The Mapk Pathwaymentioning

confidence: 59%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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“…Melanocytes are transformed to malignant melanoma cells by constitutive signal activation via a mitogen-activated protein kinase, a process that is associated with an increase in production of VEGF, supporting the hypothesis for a functional role of VEGF in melanoma transformation. 15 In this present study, we found for the first time that overexpression of PEDF decreases tumor angiogenesis and almost completely inhibits the growth of G361 melanoma xenografts in nude mice. PEDF is also known to effectively suppress retinal and choroidal neovascularization caused by ischemia and age-related macular degeneration, respectively.…”

Section: Discussionmentioning

confidence: 70%

Overexpression of Pigment Epithelium-Derived Factor Decreases Angiogenesis and Inhibits the Growth of Human Malignant Melanoma Cells in Vivo

Abe

Shimizu

Yamagishi

et al. 2004

The American Journal of Pathology

113

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Pigment epithelium-derived factor (PEDF) has recently been shown to be the most potent inhibitor of angiogenesis in the mammalian eye, and is involved in the pathogenesis of angiogenic eye disease such as proliferative diabetic retinopathy. However, a functional role for PEDF in tumor growth and angiogenesis remains to be determined. In this study, we have investigated both the in vitro and in vivo growth characteristics of human malignant melanoma G361 cell lines, stably transfected to overexpress human PEDF. Expression levels of PEDF proteins in melanoma cell lines G361 and A375 were comparable with that of human cultured melanocytes, whereas vascular endothelial growth factor levels in two tumor cell lines were much stronger than that in normal melanocytes. Overexpression of PEDF was found to significantly inhibit tumor growth and vessel formation in G361 nude mice xenografts. Furthermore, in vitro proliferation rates of G361 cells were decreased in PEDFtransfected cells. PEDF proteins showed dose-dependent induced growth retardation and apoptotic cell death in nontransfected G361 cells, which were completely prevented by treatment with antibodies against the Fas ligand. Our present study highlights two beneficial effects of PEDF treatment on melanoma growth and expansion; one is the suppression of tumor angiogenesis, and the other is induction of Angiogenesis, a process by which new vascular networks are formed from pre-existing capillaries, is required for tumors to grow, invade, and metastasize.

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“…Constitutive ERK phosphorylation is correlative with malignant transformation in many tumor cell lines including some melanoma cell populations (Kortylewski et al, 2001;Govindarajan et al, 2003). Thus, it was of interest to examine ERK activation in cells, which are resistant to ceramide and agonistic activation of Fas by the CH-11 antibody (Mel-2a and M221 cells) compared to Fas and ceramide sensitive (A-375 and M186 cells).…”

Section: Extracellular-regulated Kinase (Erk)1/2 Is Constitutively Phmentioning

confidence: 99%

Sphingosine kinase activity counteracts ceramide-mediated cell death in human melanoma cells: role of Bcl-2 expression

et al. 2005

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While most of the pharmacological therapies for melanoma utilize the apoptotic machinery of the cells, the available therapeutic options are limited due to the ability of melanoma cells to resist programmed cell death. Human melanoma cell lines A-375 and M186 are sensitive to ceramide-and Fas-induced cell death, while Mel-2a and M221 are resistant. We have now found that Mel-2a and M221 cells have a significantly higher ceramide/sphingosine-1-phosphate (S1P) ratio than A-375 and M186 cells. As sphingosine kinase (SphK) type 1 plays a critical role in determining the dynamic balance between the proapoptotic sphingolipid metabolite ceramide and the prosurvival S1P, we examined its role in apoptosis of melanoma cells. Increasing SphK1 expression reduced the sensitivity of A-375 melanoma cells to Fas-and ceramide-mediated apoptosis. Conversely, downregulation of SphK1 with small interfering RNA decreased the resistance of Mel-2a cells to apoptosis. Importantly, overexpression of the prosurvival protein Bcl-2 in A-375 cells markedly stimulated SphK1 expression and activity, while downregulation of Bcl-2 reduced SphK1 expression. This link between Bcl-2 and SphK1 might be an additional clue to chemotherapy resistance of malignant melanoma.

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Malignant Transformation of Melanocytes to Melanoma by Constitutive Activation of Mitogen-activated Protein Kinase Kinase (MAPKK) Signaling

Cited by 113 publications

References 44 publications

Role of the pro-survival molecule Bfl-1 in melanoma

Role of the pro-survival molecule Bfl-1 in melanoma

Overexpression of Pigment Epithelium-Derived Factor Decreases Angiogenesis and Inhibits the Growth of Human Malignant Melanoma Cells in Vivo

Sphingosine kinase activity counteracts ceramide-mediated cell death in human melanoma cells: role of Bcl-2 expression

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