Unfolded protein response mediated JNK/AP-1 signal transduction, a target for ovarian cancer treatment.
Researches have revealed several stressors, which could activate unfolded protein response (UPR) in cells. However, the survival or death pathway was determined by the duration of UPR exposure. Based on the UPR mediated death pathway, our study was aimed to investigate role of UPR on c-Jun N-terminal kinase (JNK)/activator protein-1 (Ap-1) signal transduction in diindolylmethane (DIM) treated ovarian cancer cell lines. Activation of UPR proteins, UPR mediated apoptotic signaling proteins and expression level of EpCAM, JNK, Ap-1, Caspase-3 and Bcl-2 were measured. Protein and gene expression, transcription factor activity, and protein phosphorylation were measured using standard molecular biology techniques. Our results demonstrated DIM treatment had significantly increased the expression of Endoplasmic reticulum (ER) stress regulators such as Bip, IRE1, CHOP and activation of UPR related apoptotic proteins in ovarian cancer cells. Decreased expression of EpCAM and activity of AP-1 transcription factor were observed in DIM treated cells. The pharmacologic inhibitors of the JNK signal transduction pathway, suggest that the impact of EpCAM expression on AP-1 transcription factor activity is mediated through the JNK pathway. Taken together, these results suggest that UPR mediated JNK/Ap-1 signal transduction has a significant role in the regulation of apoptosis in human ovarian cancer cells, and is a potential molecular target to enhance sensitivity of ovarian cancer to chemotherapy.
The Bone Marrow Transplantation Center & Multiple Myeloma Treatment Center, The First Affiliated Hospital of Medical College, Zhejiang University Hangzhou 310003, Zhejiang, China.
Gao-Feng
GF
Zheng
The Bone Marrow Transplantation Center & Multiple Myeloma Treatment Center, The First Affiliated Hospital of Medical College, Zhejiang University Hangzhou 310003, Zhejiang, China.
Zhen
Z
Cai
Department of Gynecology, The First Hospital of China Medical University Shenyang 110001, Liaoning, China.
Xiang-Kai
XK
Meng
Department of Gynecology, The First Hospital of China Medical University Shenyang 110001, Liaoning, China.
Yi
Y
Zhang
Department of Gynecology, The First Hospital of China Medical University Shenyang 110001, Liaoning, China.
Wei
W
Zhu
Department of Gynecology, The First Hospital of China Medical University Shenyang 110001, Liaoning, China.
Xiao-Yan
XY
Pang
Department of Gynecology, The First Hospital of China Medical University Shenyang 110001, Liaoning, China.
Lei
L
Dou
D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects*
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D007211:Indoles; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; C016392:3,3'-diindolylmethane
EpCAM; SKOV3 cells; diindolylmethane; endoplasmic reticulum stress