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.

RETRACTED ARTICLE: Mechanism of MALAT1 preventing apoptosis of vascular endothelial cells induced by oxygen–glucose deficiency and reoxidation

“…Caspase 3 activity, which is present in the high activity of apoptotic cells in the caspase enzyme [13], confirmed the results of this study indicate that inhibition MALAT1 OGD-Rinduced apoptosis in human brain microvascular endothelial cells. OGD-R has been reported to overproduce ROS cells, leading to apoptosis [15][16][17][18][19]. In this study, OGD-R was shown to significantly increase cellular ROS content.…”

Over-activated PD-1/PD-L1 axis facilitates the chemoresistance of diffuse large B-cell lymphoma cells to the CHOP regimen

“…As described previously (11), the activation of Akt1, the downstream effector of the PI3K, was significantly inhibited by BMK210. CHOP-induced cytotoxicity was decreased in rPD-1-treated cells, but this effect was abolished by the application of BMK210.…”

“…PD-1 binds to 2 ligands, PD-L1 and PD-L2, belonging to the B7 family (6). PD-L1 is expressed in DLBCL cells, including CRL2631 (9,11). To examine the role of PD-1/PD-L1 axis in CHOP-induced CRL2631 injury, the expression of PD-L1 was knocked down by introducing the validated siRNA that specifically targets to human PD-L1 (14).…”

Long noncoding RNA MALAT1 inhibits apoptosis induced by oxygen-glucose deprivation and reoxygenation in human brain microvascular endothelial cells

“…It has been reported that OGD-R induces cellular overproduction of ROS, which leads to cell apoptosis (15–19). In the present study, it was revealed that OGD-R significantly increased cellular ROS content.…”