PIM-1-specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosis.
Provirus integration site for Moloney murine leukemia virus (PIM1) is a proto-oncogene that encodes a serine/threonine kinase with multiple cellular functions. Overexpression of PIM-1 plays a critical role in progression of prostatic and hematopoietic malignancies. Here we describe the generation of a mAb specific for GST-PIM-1, which reacted strongly with most human and mouse cancer tissues and cell lines of prostate, breast, and colon origin but only weakly (if at all) with normal tissues. The mAb binds to PIM-1 in the cytosol and nucleus as well as to PIM-1 on the surface of human and murine cancer cells. Treatment of human and mouse prostate cancer cell lines with the PIM-1-specific mAb resulted in disruption of PIM-1/Hsp90 complexes, decreased PIM-1 and Hsp90 levels, reduced Akt phosphorylation at Ser473, reduced phosphorylation of Bad at Ser112 and Ser136, and increased cleavage of caspase-9, an indicator of activation of the mitochondrial cell death pathway. The mAb induced cancer cell apoptosis and synergistically enhanced antitumor activity when used in combination with cisplatin and epirubicin. In tumor models, the PIM-1-specific mAb substantially inhibited growth of the human prostate cancer cell line DU145 in SCID mice and the mouse prostate cancer cell TRAMP-C1 in C57BL/6 mice. These findings are important because they provide what we believe to be the first in vivo evidence that treatment of prostate cancer may be possible by targeting PIM-1 using an Ab-based therapy.
Hu
Xiu Feng
XF
Cancer Immunotherapy Laboratory, Burnet Institute Incorporating Austin Research Institute, Heidelberg, Victoria, Australia.
Li
Jie
J
Vandervalk
Scott
S
Wang
Zeping
Z
Magnuson
Nancy S
NS
Xing
Pei Xiang
PX
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000032:analysis / Q000037:antagonists & inhibitors*; D034741:RNA, Small Interfering / Q000235:genetics; D051025:bcl-Associated Death Protein / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018841:HSP90 Heat-Shock Proteins; D019869:Phosphatidylinositol 3-Kinases; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1; D034741:RNA, Small Interfering; D051025:bcl-Associated Death Protein; C000715470:MAS1 protein, human; C496634:PIM1 protein, human; C496636:Pim1 protein, mouse