Na Yoo Jin, Lee Dae-Hee, Kim Jung Lim, Kim Bo Ram, Park Seong Hye, Jo Min Jee, Jeong Soyeon, Kim Hong Jun, Lee Suk-Young, Jeong Yoon A, Oh Sang Cheul
Brain Korea 21 Program for Bio medicine Science, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea.
Brain Korea 21 Program for Bio medicine Science, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea; Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
Int J Biochem Cell Biol. 2017 Aug;89:147-156. doi: 10.1016/j.biocel.2017.06.010. Epub 2017 Jun 15.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is one of the most effective cancer treatments owing to its ability to selectively kill cancer cells, without affecting normal cells. However, it has been reported that several gastric cancer cells show resistance to TRAIL because of a scarcity of death receptor 5 (DR5) expressed on the cell surface. In this study, we show that cyclopamine sensitizes gastric cancer cells to TRAIL-induced apoptosis by elevating the expression of DR5. Interestingly, survivin hampers the existence of DR5 protein under normal conditions and cyclopamine decreases the expression of survivin, thus acting as a TRAIL sensitizer. Mechanistically, cyclopamine induces endoplasmic reticulum (ER) stress via reactive oxygen species (ROS) and CHOP, the last protein of the ER stress pathway and it regulates the proteasome degradation of survivin. Taken together, our results indicate that cyclopamine can be used for combination therapy in TRAIL-resistant gastric cancer cells.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）是最有效的癌症治疗方法之一，因为它能够选择性地杀死癌细胞，而不影响正常细胞。然而，据报道，由于一些胃癌细胞表面表达的死亡受体5（DR5）缺乏，它们对TRAIL具有抗性。在本研究中，我们表明环杷明通过提高DR5的表达使胃癌细胞对TRAIL诱导的凋亡敏感。有趣的是，生存素在正常条件下阻碍DR5蛋白的存在，而环杷明降低生存素的表达，从而作为TRAIL增敏剂发挥作用。从机制上讲，环杷明通过活性氧（ROS）和内质网应激途径的最后一种蛋白CHOP诱导内质网（ER）应激，并且它调节生存素的蛋白酶体降解。综上所述，我们的结果表明环杷明可用于对TRAIL耐药的胃癌细胞的联合治疗。
