Proteasome inhibitor MG132 inhibits angiogenesis in pancreatic cancer by blocking NF-kappaB activity.
Since angiogenesis enables solid tumors, including pancreatic cancer (PaCa), to grow and metastasize, the development of anti-angiogenic agents is currently one of the urgent issues. Proteasome inhibitors are well known for inhibiting nuclear factor-kappa B (NF-kappaB) activity in various cancer cells, but little is known about their biologic mechanisms against angiogenesis in PaCa. We divided human PaCa cell lines into high-angiogenic (BxPC-3 and SW 1990) and low-angiogenic (MIA PaCa-2 and Capan-2) groups. The high-angiogenic PaCa cell lines constitutively expressed high NF-kappaB activity and produced high levels of vascular endothelial growth factor (VEGF) and interleukin 8 (IL-8). The conditioned media from BxPC-3 significantly enhanced both proliferation of and tube formation by human umbilical vein endothelial cells (HUVECs) and these enhancements were significantly inhibited by the proteasome inhibitor MG132 treatment. Collectively, MG132 blocked PaCa-derived VEGF and IL-8 production through inhibition of NF-kappaB activity. Thus, proteasome inhibitors may prove beneficial as anti-angiogenic therapy for PaCa. Our studies show that MG132, a proteasome inhibitor, significantly blocked pancreatic-cancer-associated angiogenesis through inhibition of NF-kappaB and NF-kappaB-dependent proangiogenic gene products VEGF and IL-8.
Matsuo
Yoichi
Y
Department of Gastroenterology, Hepatology, and Nutrition, Unit 436, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
Sawai
Hirozumi
H
Ochi
Nobuo
N
Yasuda
Akira
A
Sakamoto
Masaki
M
Takahashi
Hiroki
H
Funahashi
Hitoshi
H
Takeyama
Hiromitsu
H
Guha
Sushovan
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D010179:Pancreas / Q000098:blood supply*; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D016209:Interleukin-8; D007976:Leupeptins; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde