TRAIL attenuates sulforaphane-mediated Nrf2 and sustains ROS generation, leading to apoptosis of TRAIL-resistant human bladder cancer cells

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) can preferentially initiate apoptosis in malignant cells with minimal toxicity to normal cells. Unfortunately, many human cancer cells are refractory to TRAIL-induced apoptosis through many unknown mechanisms. Here, we report that TRAIL resistance can be reversed in human bladder cancer cell lines by treatment with sulforaphane (SFN), a well-known chemopreventive isothiocyanate in various cruciferous vegetables. Combined treatment with SFN and TRAIL (SFN/TRAIL) significantly induced apoptosis concomitant with activation of caspases, loss of mitochondrial membrane potential (MMP), Bid truncation, and induction of death receptor 5. Transient knockdown of Bid prevented collapse of MMP induced by SFN/TRAIL, consequently reducing apoptotic effects. Furthermore, SFN increased both the generation of reactive oxygen species (ROS) and the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is an anti-oxidant enzyme. Interestingly, TRAIL effectively suppressed SFN-mediated nuclear translocation of Nrf2, and the period of ROS generation was more extended compared to that of treatment with SFN alone. In addition, silencing of Nrf2 increased apoptosis in cells treated with SFN/TRAIL; however, blockade of ROS generation inhibited apoptotic activity. These data suggest that SFN-induced ROS generation promotes TRAIL sensitivity and SFN can be used for the management of TRAIL-resistant cancer.

Toxicology and applied pharmacology. 2018 May 21 [Epub ahead of print]

Cheng-Yun Jin, Ilandarage Menu Neelaka Molagoda, Wisurumuni Arachchilage Hasitha Maduranga Karunarathne, Sang-Hyuck Kang, Cheol Park, Gi-Young Kim, Yung Hyun Choi

School of Pharmaceutical Science, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China., Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea., Department of Molecular Biology, College of Natural Sciences and Human Ecology, Dongeui University, Busan 67340, Republic of Korea., Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea. Electronic address: ., Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 47227, Republic of Korea. Electronic address: .

email news signup