Sulforaphane induces apoptosis in T24 human urinary bladder cancer cells through a reactive oxygen species-mediated mitochondrial pathway: The involvement of endoplasmic reticulum stress and the Nrf2 signaling pathway

• Published in: International journal of oncology Vol. 45; no. 4; pp. 1497 - 1506
• Main Authors: JO, GUK HEUI, KIM, GI-YOUNG, KIM, WUN-JAE, PARK, KUN YOUNG, CHOI, YUNG HYUN
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.10.2014; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Bladder cancer; Cancer therapies; Care and treatment; Cell Line, Tumor; Cellular signal transduction; Cytochrome; Deoxyribonucleic acid; DNA; Endoplasmic reticulum; endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Humans; Isothiocyanates - pharmacology; Kinases; Life sciences; Medical prognosis; Mitochondria; Mitochondria - metabolism; Morphology; NF-E2-Related Factor 2 - metabolism; nuclear factor-E2-related factor-2; Patient outcomes; Physiological aspects; Physiology; Phytochemicals; Proteins; reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; sulforaphane; Transcription factors; Tumors; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2014.2536

Sulforaphane, a naturally occurring isothiocyanate found in cruciferous vegetables, has received a great deal of attention because of its ability to inhibit cell proliferation and induce apoptosis in cancer cells. In this study, we investigated the anticancer activity of sulforaphane in the T24 human bladder cancer line, and explored its molecular mechanism of action. Our results showed that treatment with sulforaphane inhibited cell viability and induced apoptosis in T24 cells in a concentration-dependent manner. Sulforaphane-induced apoptosis was associated with mitochondria dysfunction, cytochrome c release and Bcl-2/Bax dysregulation. Furthermore, the increased activity of caspase-9 and -3, but not caspase-8, was accompanied by the cleavage of poly ADP-ribose polymerase, indicating the involvement of the mitochondria-mediated intrinsic apoptotic pathway. Concomitant with these changes, sulforaphane triggered reactive oxygen species (ROS) generation, which, along with the blockage of sulforaphane-induced loss of mitochondrial membrane potential and apoptosis, was strongly attenuated by the ROS scavenger N-acetyl-L-cysteine. Furthermore, sulforaphane was observed to activate endoplasmic reticulum (ER) stress and the nuclear factor-E2-related factor-2 (Nrf2) signaling pathway, as demonstrated by the upregulation of ER stress-related proteins, including glucose-regulated protein 78 and C/EBP-homologous protein, and the accumulation of phosphorylated Nrf2 proteins in the nucleus and induction of heme oxygenase-1 expression, respectively. Taken together, these results demonstrate that sulforaphane has antitumor effects against bladder cancer cells through an ROS-mediated intrinsic apoptotic pathway, and suggest that ER stress and Nrf2 may represent strategic targets for sulforaphane-induced apoptosis.