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 (TRAF2DeltaN), increases activities of
p38 MAPK, ATF2, and the level of
TNFalpha expression. Forced expression of TRAF2DeltaN in HHMSX highly metastatic
melanoma cells that lack Fas expression and thus utilize the TNFalpha-TNFR1 as the major apoptotic pathway sensitized cells to UV-induced apoptosis. An over twofold increase in degree of apoptosis was observed in TRAF2DeltaN expressing cells that were treated with
actinomycin D,
anisomycin or with the radiomimetic
drug neocarzinostatin. Sensitization by TRAF2DeltaN is selective since it was not observed in response to either
Taxol or
cis-platinum treatment. TRAF2DeltaN 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 TRAF2DeltaN, indicating that p38-mediated suppression of
NF-kappaB activity is among TRAF2DeltaN effects. Our finding identifies p38,
TNFalpha and
NF-kappaB 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.