Abstract
Mechanisms underlying radiation and chemotherapy resistance, the hallmark of human melanoma, are not well understood. Here we demonstrate that expression levels of signal adaptor protein TRAF2 coincide with melanoma resistance to UV-irradiation. Altered TRAF2 signaling by a form of TRAF2, which lacks the ring finger domain (TRAF2ΔN), increases activities of p38 MAPK, ATF2, and the level of TNFα expression. Forced expression of TRAF2ΔN in HHMSX highly metastatic melanoma cells that lack Fas expression and thus utilize the TNFα-TNFR1 as the major apoptotic pathway sensitized cells to UV-induced apoptosis. An over twofold increase in degree of apoptosis was observed in TRAF2ΔN expressing cells that were treated with actinomycin D, anisomycin or with the radiomimetic drug neocarzinostatin. Sensitization by TRAF2ΔN is selective since it was not observed in response to either Taxol or cis-platinum treatment. TRAF2ΔN effects are primarily mediated via p38 since inhibition of p38 reduces, whereas activation of p38 promotes the level of UV-induced apoptosis. Conversely, activation of IKK attenuates the sensitization of melanoma by TRAF2ΔN, indicating that p38-mediated suppression of NF-κB activity is among TRAF2ΔN effects. Our finding identifies p38, TNFα and NF-κB among key players that efficiently sensitizes melanoma cells to UV-, ribotoxic (anisomycin) and radiomimetic chemicals-induced programmed cell death in response to aberrant TRAF2 signaling.
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Abbreviations
- AP1:
-
activator protein-1
- ATF2:
-
activating transcription factor 2
- NF-κB:
-
nuclear factor kappa B
- IKK:
-
inhibitor nuclear factor kappa B kinase
- PI:
-
propidium iodide
- TNFα:
-
tumor necrosis factor alpha
- TNFR:
-
tumor necrosis factor receptor
- TRAF2:
-
tumor necrosis factor receptor associated factor 2
- GFP:
-
green fluorescent protein
- IκB:
-
inhibitor NF-κB
- MAPK:
-
mitogen-activated protein kinase
- MFI:
-
medium fluorescence intensity
- MKK:
-
MAPK kinase
- CHX:
-
cycloheximide
- NCS:
-
neocarzinostatin
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Acknowledgements
We thank Drs H van Dam, JS Economou, M Karin and R Davis for providing expression vectors and Dr M Herlyn for LU1205 and WM1552 melanoma cells. Support from the National Cancer Institute through grant CA 51995 (to Z Ronai) is gratefully acknowledged.
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Ivanov, V., Fodstad, Ø. & Ronai, Z. Expression of ring finger-deleted TRAF2 sensitizes metastatic melanoma cells to apoptosis via up-regulation of p38, TNFα and suppression of NF-κB activities. Oncogene 20, 2243–2253 (2001). https://doi.org/10.1038/sj.onc.1204314
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DOI: https://doi.org/10.1038/sj.onc.1204314
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