Many cancer cells are resistant to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), thus treatment with TRAIL in combination with other agents might be an effective strategy to overcome the resistance. Luteolin is a flavonoid rich in diets and some medicinal plants. Here we found that pretreatment with a non-cytotoxic concentration of luteolin significantly sensitized TRAIL-induced apoptosis in both TRAIL-sensitive (HeLa) and TRAIL-resistant cancer cells (CNE1, HT29 and HepG2). Such sensitization is achieved through enhanced caspase 8 activation and caspase 3 maturation, without affecting the expression of death receptors (DR4, DR5, DcR1 or DcR2) on the cell surface. Further, the protein level of X-linked inhibitor of apoptosis protein (XIAP) was markedly reduced in cells treated with luteolin and TRAIL, and ectopic expression of XIAP abolished the cell death. Interestingly, XIAP down-regulation was prevented by MG132, a protease inhibitor, suggesting that it was achieved through enhanced ubiquitination and proteasomal degradation. We further demonstrated that protein kinase C (PKC) activation prevented cell death induced by luteolin and TRAIL via suppression of XIAP down-regulation. Moreover, luteolin inhibited PKC activity and bisindolylmaleimide I (BIM), a general PKC inhibitor, simulated luteolin in sensitizing TRAIL-induced apoptosis. Taken together, these results present a novel anti-cancer effect of luteolin and support its potential application in cancer therapy in combination with TRAIL. In addition, our data reveal a new function of PKC in cell death: PKC activation stabilizes XIAP and thus suppresses TRAIL-induced apoptosis.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]