Carnitine sensitizes TRAIL-resistant cancer cells to TRAIL-induced apoptotic cell death through the up-regulation of Bax.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family with apoptosis-inducing activity. Given that TRAIL selectively induces cell death in various tumors but has little or no toxicity to normal cells, TRAIL agonists have been considered as promising anti-cancer therapeutic agents. However, the resistance of many primary tumors and cancer cells to TRAIL poses a challenge. In our present study, we found that carnitine, a metabolite that transfers long-chain fatty acids into mitochondria for beta-oxidation and modulates protein kinase C activity, sensitizes TRAIL-resistant cancer cells to TRAIL. Combination of carnitine and TRAIL was found to synergistically induce apoptotic cell death through caspase activation, which was blocked by a pan caspase inhibitor, but not by an inhibitor of autophagy or an inhibitor of necrosis. The combination of carnitine and TRAIL reversed the resistance to TRAIL in lung cancer cells, colon carcinoma cells, and breast carcinoma cells. We further demonstrate that carnitine, either alone or in combination with TRAIL, enhances the expression of the pro-apoptotic Bcl-2 family protein, Bcl-2-associated X protein (Bax). The down-regulation of Bax expression by small interfering RNA reduced caspase activation when cells were treated with TRAIL, and experiments with cells from Bax knockout mice confirmed this result. Taken together, our current results suggest that carnitine can reverse the resistance of cancer cells to TRAIL by up-regulating Bax expression. Thus, a combined delivery of carnitine and TRAIL may represent a new therapeutic strategy to treat TRAIL-resistant cancer cells.
Graduate School of East-West Medical Science, Kyung Hee University, Gyeoggi-do, South Korea.
So Jung
SJ
Park
Seong Ho
SH
Park
Joo-Oh
JO
Kim
Jung Ho
JH
Kim
So Jung
SJ
Park
Jung Jin
JJ
Hwang
Dong-Hoon
DH
Jin
Seong-Yun
SY
Jeong
Seung Jin
SJ
Lee
Jin Cheon
JC
Kim
Inki
I
Kim
Dong-Hyung
DH
Cho
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002331:Carnitine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis* / Q000235:genetics
D053221:TNF-Related Apoptosis-Inducing Ligand; D051028:bcl-2-Associated X Protein; D002331:Carnitine