title: 3,3'-Diindolylmethane potentiates paclitaxel-induced antitumor effects on gastric cancer cells through the Akt/FOXM1 signaling cascade.
abstract: Gastric cancer is the fourth most common cancer and is one of the leading causes of cancer-related mortality worldwide. Forkhead box M1 (FOXM1) is overexpressed in gastric cancer, suggesting that it is important in gastric cancer oncogenesis. However, no studies have investigated the role of 3,3'-diindolylmethane (DIM), a component of cruciferous vegetables, in the regulation of FOXM1 and its signaling pathway in gastric cancer. Here, we report for the first time that DIM effectively downregulated Akt/FOXM1 in gastric cancer cells. Combination treatment with DIM and paclitaxel significantly and dose-dependently inhibited the proliferation of SNU638 cells when compared to treatment with DIM or paclitaxel alone. Colony formation of SNU638 cells was significantly attenuated by treatment with DIM and paclitaxel, and DIM potentiated the inhibition of colony formation in SNU638 cells by paclitaxel when compared to treatment with a single agent. Treatment with DIM plus paclitaxel substantially increased apoptosis as indicated by increased levels of cleaved polyADP-ribose polymerase (PARP) and cleaved caspase-9 protein. DIM dose-dependently sensitized gastric cancer cells through downregulation of FOXM1 and potentiated the effects of paclitaxel. FOXM1 effector genes such as CDK4, p53 and cyclin D1 were downregulated in gastric cancer cells by combination treatment with DIM and paclitaxel. In addition, DIM significantly and dose-dependently inhibited phosphorylation of Akt and potentiated paclitaxel-induced inhibition of Akt function in gastric cancer cells. Therefore, our results indicate that DIM effectively potentiates the efficacy of chemotherapeutic agents such as paclitaxel by downregulation of the Akt/FOXM1 signaling cascade in gastric cancer cells. Our findings suggest that DIM enhances the therapeutic efficacy of paclitaxel in gastric cancer and is a potential clinical anticancer agent for the prevention and/or treatment of gastric cancer.
authors: Department of Physiology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors: Hua
authors: H
authors: Jin
authors: Catholic University of Pusan, Busan, Republic of Korea.
authors: Man Hee
authors: MH
authors: Park
authors: Department of Physiology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors: Soo Mi
authors: SM
authors: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9 / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C530104:CCND1 protein, human; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D007211:Indoles; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D053453:Caspase 9; D017239:Paclitaxel; C016392:3,3'-diindolylmethane