Arsenic trioxide, retinoic acid and Ara-c regulated the expression of annexin II on the surface of APL cells, a novel co-receptor for plasminogen/tissue plasminogen activator.
Annexin II (AnnII), a high-affinity co-receptor for plasminogen/tissue plasiminogen activator, plays a central role in the primary hyperfibrinolysis in acute promyelocytic leukemia (APL). The aberrant expression of annexin II was found on the APL cell surface in the present study. We investigated patients with APL receiving all-trans retinoic acid (ATRA) or arsenic trioxide (As(2)O(3)) treatment, contributing to the downregulation of the expression of annexin II on APL cells, and decreasing the generation of plasmin by tissue plasminogen activator (t-PA). Notably, the clinical improvement of hyperfibrinolysis paralleled the correction of plasma fibrinogen level and amelioration of bleeding. Consistent with in vivo findings, annexin II on NB(4) cell surface and its mRNA content were downregulated with 1 microM As(2)O(3) or 1 microM ATRA, while 2 microg Ara-c enhanced the expression of annexin II and the generation of cell-surface plasmin before its induction of apoptosis. Our data indicate that the inhibition of annexin II expression with ATRA is transcriptionally mediated while As(2)O(3) induces an accelerated degradation of annexin II mRNA. Western blot analysis under treatment conditions showed that both ATRA and As(2)O(3) markedly decreased the production of annexin II, reaching a level near the baseline at 5 and 7 days after treatment, respectively. Annexin II expression of APL cells may be downregulated by ATRA and As(2)O(3.) Therefore, both agents improve hyperfibrinolysis-related hemorrhage of APL, which induced APL cells to difference and apoptosis, respectively.
Zhang
Xiaohui
X
Department of Hematology, Union Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, PR China.
Zhou
Huarong
H
Wang
Jun
J
Yang
Linhua
L
Hu
Yu
Y
Shen
Guanxin
G
Guo
Peixue
P
Qiao
Zhenhua
Z
Song
Shanjun
S
D000293:Adolescent; D000328:Adult; D017306:Annexin A2 / Q000032:analysis* / Q000187:drug effects / Q000235:genetics; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051777:AraC Transcription Factor; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000494:pharmacology; D001426:Bacterial Proteins; D005260:Female; D005341:Fibrinolysin / Q000096:biosynthesis / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006470:Hemorrhage / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010087:Oxides / Q000008:administration & dosage / Q000494:pharmacology; D010960:Plasminogen Activators / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects; D012097:Repressor Proteins / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014157:Transcription Factors; D014162:Transfection; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D017306:Annexin A2; D000970:Antineoplastic Agents; D051777:AraC Transcription Factor; D001152:Arsenicals; D001426:Bacterial Proteins; D010087:Oxides; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D014212:Tretinoin; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D000077237:Arsenic Trioxide