Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an 
important member of the TNF superfamily with great potential in cancer therapy. 
Luteolin is a dietary flavonoid commonly found in some medicinal plants. Here we 
found that pretreatment with a noncytotoxic 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. 
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 protected against cell death induced by luteolin and TRAIL, 
showing that luteolin sensitizes TRAIL-induced apoptosis through down-regulation 
of XIAP. In search of the molecular mechanism responsible for XIAP 
down-regulation, we found that luteolin and TRAIL promoted XIAP ubiquitination 
and proteasomal degradation. Next, we showed 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, a general PKC inhibitor, simulated luteolin in 
sensitizing TRAIL-induced apoptosis. Taken together, these results present a 
novel anticancer 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.