title: Curcumin enhances TRAIL-induced apoptosis of breast cancer cells by regulating apoptosis-related proteins.
abstract: The TNF-related apoptosis inducing ligand (TRAIL) has promising anti-cancer therapeutic activity, although significant percentage of primary tumors resistant to TRAIL-induced apoptosis remains an obstacle to the extensive use of TRAIL-based mono-therapies. Natural compound curcumin could potentially sensitize resistant cancer cells to TRAIL. We found that the combination of TRAIL with curcumin can synergistically induces apoptosis in three TRAIL-resistant breast cancer cell lines. The mechanism behind this synergistic cell death was investigated by examining an effect of curcumin on the expression and activation of TRAIL-associated cell death proteins. Immunoblotting, RNA interference, and use of chemical inhibitors of TRAIL-activate signaling revealed differential effects of curcumin on the expression of Mcl-1 and activities of ERK and Akt. Curcumin-induced production of reactive oxygen species did not affect total expression of DR5 but it enhanced mobilization of DR5 to the plasma membrane. In these breast cancer cells curcumin also induced downregulation of IAP proteins. Taken together, our data suggest that a combination of TRAIL and curcumin is a potentially promising treatment for breast cancer, although the specific mechanisms involved in this sensitization could differ even among breast cancer cells of different origins.
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, 138-736, Republic of Korea.
authors.forename: Sojung
authors.initials: S
authors.lastname: Park
authors.forename: Dong Hyung
authors.initials: DH
authors.lastname: Cho
authors.forename: Ladislav
authors.initials: L
authors.lastname: Andera
authors.forename: Nayoung
authors.initials: N
authors.lastname: Suh
authors.forename: Inki
authors.initials: I
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D003474:Curcumin