OBJECTIVE: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is thought to be a promising anti-neoplastic agent because of its ability to selectively induce apoptosis in cancer cells. However, some cancer cells are resistant to TRAIL. The mechanisms underlying this resistance are unclear. The aim of this study was to explore the role of programmed cell death 4 (PDCD4) in regulating TRAIL sensitivity in gastric cancer cells. METHODS: PDCD4 complementary DNA and PDCD4-specific short-hairpin RNA (shRNA) fragments were transfected into TRAIL-sensitive and -resistant gastric cancer cells. Expression of PDCD4 and Akt was detected via western blot. Cell survival and apoptosis were measured using 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry (FCM) assays. RESULTS: We found that upregulation of PDCD4 enhanced TRAIL sensitivity in gastric cancer cells. Downregulation of PDCD4 decreased TRAIL sensitivity. Inhibition of Akt by the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 induced PDCD4 activity and enhanced TRAIL sensitivity in TRAIL-resistant gastric cancer cells. CONCLUSION: We demonstrated that PDCD4 regulates TRAIL sensitivity in gastric cancer cells by inhibiting the PI3K/Akt signaling pathway.
OBJECTIVE:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is thought to be a promising anti-neoplastic agent because of its ability to selectively induce apoptosis in cancer cells. However, some cancer cells are resistant to TRAIL. The mechanisms underlying this resistance are unclear. The aim of this study was to explore the role of programmed cell death 4 (PDCD4) in regulating TRAIL sensitivity in gastric cancer cells. METHODS:PDCD4 complementary DNA and PDCD4-specific short-hairpin RNA (shRNA) fragments were transfected into TRAIL-sensitive and -resistant gastric cancer cells. Expression of PDCD4 and Akt was detected via western blot. Cell survival and apoptosis were measured using 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry (FCM) assays. RESULTS: We found that upregulation of PDCD4 enhanced TRAIL sensitivity in gastric cancer cells. Downregulation of PDCD4 decreased TRAIL sensitivity. Inhibition of Akt by the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 induced PDCD4 activity and enhanced TRAIL sensitivity in TRAIL-resistant gastric cancer cells. CONCLUSION: We demonstrated that PDCD4 regulates TRAIL sensitivity in gastric cancer cells by inhibiting the PI3K/Akt signaling pathway.
Authors: J L Cmarik; H Min; G Hegamyer; S Zhan; M Kulesz-Martin; H Yoshinaga; S Matsuhashi; N H Colburn Journal: Proc Natl Acad Sci U S A Date: 1999-11-23 Impact factor: 11.205
Authors: H Thakkar; X Chen; F Tyan; S Gim; H Robinson; C Lee; S K Pandey; C Nwokorie; N Onwudiwe; R K Srivastava Journal: J Biol Chem Date: 2001-07-18 Impact factor: 5.157
Authors: Alexey Palamarchuk; Alexey Efanov; Vadim Maximov; Rami I Aqeilan; Carlo M Croce; Yuri Pekarsky Journal: Cancer Res Date: 2005-12-15 Impact factor: 12.701