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Carcinogenesis Advance Access published online on December 20, 2006
Carcinogenesis, doi:10.1093/carcin/bgl251
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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Sulforaphane sensitizes tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis through downregulation of ERK and Akt in lung adenocarcinoma A549 cells

Cheung-Yun Jin1,{dagger}, Dong-Oh Moon2,{dagger}, Jae-Dong Lee1, Moon-Soo Heo2, Yung Hyun Choi3, Chang-Min Lee4, Yeong-Min Park4,* and Gi-Young Kim2,*

1 Department of Microbiology, Pusan National University, Busan 614-052, South Korea
2 Faculty of Applied Marine Science, Cheju National University, Jeju 690-756, South Korea
3 Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052, South Korea
4 Department of Microbiology and Immunology & National Research Laboratory of Dendritic Cell Differentiation & Regulation, and Medical Research Institute, Pusan National University College of Medicine, Busan 602-739, South Korea

* To whom correspondence should be addressed. Tel: +82 64 754 3427; Fax: +82 64 756 3493; Email: immunkim{at}cheju.ac.kr (G.-Y. Kim). Tel: +82 51 243 2259; Fax: +82 51 256 2269; Email: immunpym{at}pusan.ac.kr (Y.-M. Park).

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-G1 phase DNA content. These indicators of apoptosis correlate with the induction of caspase-3 activity, which results in the cleavage of poly(ADP-ribose)polymerase (PARP) and the release of lactate dehydrogenase (LDH). 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.

{dagger} These authors contributed equally to this work.


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