Recent Advances in Melanoma Biology

“…However, only limited therapies for metastatic stage of the disease are currently available. Various attempts have been made to restore high levels of apoptosis in response to treatment for this type of cancer [4][5][6]. One of the key contributors to radio-and chemoresistance of human melanomas is upregulation of transcription factors STAT3 and NF-κB, which control expression of numerous antiapoptotic genes in cancer cells, including cFLIP, cIAP, XIAP, Bcl-xL, Survivin, as well as suppressing proapoptotic genes [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

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Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/ DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-κB that control the expression of antiapoptotic genes, including cFLIP and BclxL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-κB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while γ-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by γ-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas.

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“…Furthermore, human melanomas actively suppress the immune system [18][19][20]. Despite the dramatic increase in the incidence of this tumor in the past decades, the molecular mechanisms of its progression and resistance to apoptosis remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Despite the dramatic increase in the incidence of this tumor in the past decades, the molecular mechanisms of its progression and resistance to apoptosis remain largely unknown. Melanoma cells express many different growth factors, cytokines and their receptors (including TNFα/TNFR1) for regulation of their growth and progression [19,21]. Tumor necrosis factor alpha (TNFα) mediates a variety of biological functions such as cell proliferation, differentiation and cell death.…”

Section: Introductionmentioning

confidence: 99%

Dual treatment with COX-2 inhibitor and sodium arsenite leads to induction of surface Fas Ligand expression and Fas-Ligand-mediated apoptosis in human melanoma cells

Ivanov¹,

Hei²

2006

Experimental Cell Research

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Most human melanomas express Fas receptor on the cell surface, and treatment with exogenous Fas Ligand (FasL) efficiently induces apoptosis of these cells. In contrast, endogenous surface expression of FasL is suppressed in Fas-positive melanomas. We report here the use of a combination of sodium arsenite, an inhibitor of NF-κB activation, and NS398, a cyclooxygenase-2 (COX-2) inhibitor, for restoration of the surface FasL expression. We observed a large increase of Fas-mediated apoptosis in Fas-positive melanomas. This was due to induction of FasL surface expression and increased susceptibility to Fas death signaling after arsenite and NS398 treatment. Furthermore, silencing COX-2 expression by specific RNAi also effectively increased surface FasL expression following arsenite treatment. Upregulation of the surface FasL levels was based on an increase in the efficiency of translocation to the cell surface and stabilization of FasL protein on the cell surface, rather than on acceleration of the FasL gene transcription. Data obtained demonstrate that the combination of arsenite with inhibitors of COX-2 may affect the target cancer cells via induction of FasL-mediated death signaling.

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Recent Advances in Melanoma Biology

Cited by 66 publications

References 30 publications

2D-DIGE analysis of phospho-enriched fractions from dasatinib-treated melanoma cell lines

2D-DIGE analysis of phospho-enriched fractions from dasatinib-treated melanoma cell lines

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Dual treatment with COX-2 inhibitor and sodium arsenite leads to induction of surface Fas Ligand expression and Fas-Ligand-mediated apoptosis in human melanoma cells

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