title: Sensitization of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant primary prostate cancer cells by isoegomaketone from Perilla frutescens.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is currently in clinical trials as a cancer treatment due to its ability to induce apoptosis selectively in cancer cells. Nevertheless, the risk of developing resistance warrants the development of sensitizers that can overcome resistance to TRAIL. In this study, isoegomaketone (1) acted as a synergistic TRAIL sensitizer by mediating up-regulation of DR5 expression in primary prostate cancer RC-58T/h/SA#4 cells. Combined with 1, TRAIL exhibited enhanced apoptotic activity in a human prostate cancer cell line designated RC-58T/h/SA#4, as indicated by increases in annexin V-positive and sub-G1 cell populations as well as condensation of chromatin or apoptotic bodies. Combined treatment also activated caspases-8, -9, and -3; increased the protein levels of Bax, AIF, and cytosolic cytochrome c; and induced PARP cleavage while reducing Bcl-2 protein expression. Human recombinant DR5 Fc chimera efficiently attenuated 1-induced apoptosis, thereby demonstrating the critical role of DR5 in 1-mediated apoptotic cell death. Furthermore, DR5 expression induced by 1 was mediated via a ROS-independent pathway that required CHOP and p53. Overall, these findings provide evidence that 1 potentiates TRAIL-mediated apoptosis through up-regulation of DR5 via a ROS-independent pathway. This suggests that 1 has potential for increasing the effectiveness of prostate cancer therapy with TRAIL.
authors.affiliation: Department of Food and Nutrition and ‡Research Institute of Basic Science, Sunchon National University , Suncheon 540-742, Republic of Korea.
authors.forename: Ju-Hye
authors.initials: JH
authors.lastname: Lee
authors.forename: Hyun-Dong
authors.initials: HD
authors.lastname: Cho
authors.forename: Il-Yun
authors.initials: IY
authors.lastname: Jeong
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Lee
authors.forename: Kwon-Il
authors.initials: KI
authors.lastname: Seo
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D005663:Furans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D031344:Perilla frutescens / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D005663:Furans; D007659:Ketones; D053221:TNF-Related Apoptosis-Inducing Ligand; C568138:isoegomaketone; D053181:Caspase 8