title: Annexin A5 inhibits diffuse large B-cell lymphoma cell invasion and chemoresistance through phosphatidylinositol 3-kinase signaling.
abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma worldwide. Although patient outcomes have significantly improved to a greater than 40% cure rate by the combinatorial cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy, which is widely used, resistance to the CHOP regimen continues to pose a problem in managing or curing DLBCL. While it promotes the malignancy and chemo-resistance in certain types of cancer, Annexin A5 is negatively correlated with those in other cancers, including DLBCL. In the present study, we explored the effects of Annexin A5 on DLBCL cell invasion and chemoresistance to CHOP. Stable overexpression and knockdown of Annexin A5 were performed in Toledo and Pfeiffer human DLBCL cell lines. Overexpression of Annexin A5 in both cell lines significantly decreased cell invasion, matrix metalloproteinase-9 (MMP-9) expression/activity, phosphatidylinositol 3-kinase (PI3K) activity/Akt phosphorylation, and cell survival against CHOP-induced apoptosis. On the other hand, knockdown of Annexin A5 markedly increased cell invasion, MMP-9 expression/activity, PI3K activity/Akt phosphorylation, and CHOP-induced apoptosis in the DLBCL cell lines, which was abolished by selective PI3K inhibitor BKM120. In conclusion, our study provides the first in vitro evidence that Annexin A5 inhibits DLBCL cell invasion, MMP-9 expression/activity, and chemoresistance to CHOP through a PI3K-dependent mechanism; it provides new insight not only into the biological function of Annexin A5, but also into the molecular mechanisms underlying DLBCL progression and chemoresistance.
authors.affiliation: Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Xianling
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Jinan
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Guangsen
authors.initials: G
authors.lastname: Zhang
mesh_terms: D017304:Annexin A5 / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011241:Prednisone / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014750:Vincristine / Q000494:pharmacology
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D011241:Prednisone