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Proteasome Inhibitor MG132 Inhibits Angiogenesis in Pancreatic Cancer by Blocking NF-κB Activity

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Abstract

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-κB) 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-κB 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-κB 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-κB and NF-κB-dependent proangiogenic gene products VEGF and IL-8.

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Abbreviations

PaCa:

Pancreatic cancer

NF-κB:

Nuclear factor-kappa B

VEGF:

Vascular endothelial growth factor

IL:

Interleukin

FCS:

Fetal calf serum

HUVEC:

Human umbilical vein endothelial cell

MTS assay:

Celltiter 96 Aqueous One Solution cell proliferation assay

ELISA:

Enzyme-linked immunosorbent assay

EMSA:

Electrophoretic mobility shift assay

ANOVA:

Analysis of variance

SD:

Standard deviation

SNK test:

Student–Newman–Keuls test

PI:

Proteasome inhibitor

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Acknowledgments

The authors would like to thank Karen Phillips from the Department of Scientific Publications for carefully reviewing this manuscript. This research was supported in part by The University of Texas M.D. Anderson Cancer Center Physician Scientist Program Award (to SG) and NIH grant CA16672 (Cancer Center Support Grant to M.D. Anderson Cancer Center).

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Authors and Affiliations

  1. Department of Gastroenterology, Hepatology, and Nutrition, Unit 436, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Yoichi Matsuo, Nobuo Ochi & Sushovan Guha

  2. Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Yoichi Matsuo, Hirozumi Sawai, Nobuo Ochi, Akira Yasuda, Masaki Sakamoto, Hiroki Takahashi, Hitoshi Funahashi & Hiromitsu Takeyama

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  1. Yoichi Matsuo
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  2. Hirozumi Sawai
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Correspondence to Sushovan Guha.

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Matsuo, Y., Sawai, H., Ochi, N. et al. Proteasome Inhibitor MG132 Inhibits Angiogenesis in Pancreatic Cancer by Blocking NF-κB Activity. Dig Dis Sci 55, 1167–1176 (2010). https://doi.org/10.1007/s10620-009-0814-4

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