title: Sulforaphane sensitizes tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis through downregulation of ERK and Akt in lung adenocarcinoma A549 cells.
abstract: The cytotoxic effect of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is limited in some cancer cells, including A549 lung adenocarcinoma cells. However, treatment with TRAIL in combination with subtoxic concentrations of sulforaphane (SFN) sensitizes TRAIL-resistant A549 cells to TRAIL-mediated apoptosis. Combined treatment with SFN and TRAIL induced chromatin condensation, DNA fragmentation, annexin V staining and sub-G(1) phase DNA content. These indicators of apoptosis correlate with the induction of caspase-3 activity that results in the cleavage of poly(ADP-ribose) polymerase and the release of lactate dehydrogenase. Both the cytotoxic effect and apoptotic characteristics induced by combined treatment were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, demonstrating the important role of caspase-3 in the observed cytotoxic effect. Combined treatment also triggered the activation of p38 MAPK and JNK, and downregulation of ERK and Akt. Inhibitors of ERK (PD98059) or Akt (LY294002), but not p38 MAPK, resulted in significantly decreased cell viability. Although the activation of JNK was increased in response to combined treatment, inhibition of the JNK pathway significantly attenuated cell viability. These results indicate that caspase-3 is a key regulator of apoptosis in response to combined SFN and TRAIL in human lung adenocarcinoma A549 cells through downregulation of ERK and Akt.
authors.affiliation: Department of Microbiology, Pusan National University, Busan 614-052, South Korea.
authors.forename: Cheung-Yun
authors.initials: CY
authors.lastname: Jin
authors.forename: Dong-Oh
authors.initials: DO
authors.lastname: Moon
authors.forename: Jae-Dong
authors.initials: JD
authors.lastname: Lee
authors.forename: Moon-Soo
authors.initials: MS
authors.lastname: Heo
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Lee
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Park
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D017879:Isothiocyanates; D008175:Lung Neoplasms / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013454:Sulfoxides; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D013861:Thiocyanates / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha
chemical_list: D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D013454:Sulfoxides; D053221:TNF-Related Apoptosis-Inducing Ligand; D013861:Thiocyanates; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; C016766:sulforaphane