The effect of disintegrin-metalloproteinase ADAM9 in gastric cancer progression

Jeong Min Kim, Hei Cheul Jeung, Sun Young Rha, Eun Jeong Yu, Tae Soo Kim, You Keun Shin, Xianglan Zhang, Kyu Hyun Park, Seung Woo Park, Hyun Cheol Chung, Garth Powis

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Advanced gastric cancer is one of the most aggressive gastrointestinal malignancies, and ADAM (A disintegrin and metalloproteinase)-9 is a cell-surface membrane glycoprotein with oncogenic properties that is overexpressed in several cancers. Herein, we investigated the biologic mechanism of ADAM9 in the progression, proliferation, and invasion of gastric cancer. First, we detected ADAM's expression, processing, and protease activity in gastric cancer cells. Protease activity was moderately correlated with ADAM9 protein expression, but was better related to a processed smaller molecular weight (84 kDa) form of ADAM9. Knockdown of ADAM9 or specifically targeted monoclonal antibody (RAV-18) suppressed cancer cell proliferation and invasion in high ADAM9-expressing cells, not in low ADAM9-expressing cells. RAV-18 showed in vivo antitumor activity in a gastric cancer xenograft model. Hypoxia (1% oxygen) induced ADAM9 expression and functional activity in low ADAM9-expressing gastric cancer cells that was inhibited by siRNA knockdown or RAV-18 antibody to levels in normoxic cells. Overall, our studies show that ADAM9 plays an important role in gastric cancer proliferation and invasion, and that while expressed in some gastric cancer cells at high levels that are responsive to functional inhibition and antitumor activity of a catalytic site-directed antibody, other gastric cancer cells have low levels of expression and only when exposed to hypoxia do ADAM9 levels increase and the cells become responsive to ADAM9 antibody inhibition. Therefore, our findings suggest that ADAM9 could be an effective therapeutic target for advanced gastric cancer.

Original languageEnglish
Pages (from-to)3074-3085
Number of pages12
JournalMolecular Cancer Therapeutics
Volume13
Issue number12
DOIs
Publication statusPublished - 2014 Dec 1

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Disintegrins
Metalloproteases
Stomach Neoplasms
Membrane Glycoproteins
Antibodies
Peptide Hydrolases
Neoplasms
Heterografts
Small Interfering RNA
Catalytic Domain
Molecular Weight
Monoclonal Antibodies
Cell Proliferation
Cell Membrane
Oxygen

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kim, Jeong Min ; Jeung, Hei Cheul ; Rha, Sun Young ; Yu, Eun Jeong ; Kim, Tae Soo ; Shin, You Keun ; Zhang, Xianglan ; Park, Kyu Hyun ; Park, Seung Woo ; Chung, Hyun Cheol ; Powis, Garth. / The effect of disintegrin-metalloproteinase ADAM9 in gastric cancer progression. In: Molecular Cancer Therapeutics. 2014 ; Vol. 13, No. 12. pp. 3074-3085.
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abstract = "Advanced gastric cancer is one of the most aggressive gastrointestinal malignancies, and ADAM (A disintegrin and metalloproteinase)-9 is a cell-surface membrane glycoprotein with oncogenic properties that is overexpressed in several cancers. Herein, we investigated the biologic mechanism of ADAM9 in the progression, proliferation, and invasion of gastric cancer. First, we detected ADAM's expression, processing, and protease activity in gastric cancer cells. Protease activity was moderately correlated with ADAM9 protein expression, but was better related to a processed smaller molecular weight (84 kDa) form of ADAM9. Knockdown of ADAM9 or specifically targeted monoclonal antibody (RAV-18) suppressed cancer cell proliferation and invasion in high ADAM9-expressing cells, not in low ADAM9-expressing cells. RAV-18 showed in vivo antitumor activity in a gastric cancer xenograft model. Hypoxia (1{\%} oxygen) induced ADAM9 expression and functional activity in low ADAM9-expressing gastric cancer cells that was inhibited by siRNA knockdown or RAV-18 antibody to levels in normoxic cells. Overall, our studies show that ADAM9 plays an important role in gastric cancer proliferation and invasion, and that while expressed in some gastric cancer cells at high levels that are responsive to functional inhibition and antitumor activity of a catalytic site-directed antibody, other gastric cancer cells have low levels of expression and only when exposed to hypoxia do ADAM9 levels increase and the cells become responsive to ADAM9 antibody inhibition. Therefore, our findings suggest that ADAM9 could be an effective therapeutic target for advanced gastric cancer.",
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Kim, JM, Jeung, HC, Rha, SY, Yu, EJ, Kim, TS, Shin, YK, Zhang, X, Park, KH, Park, SW, Chung, HC & Powis, G 2014, 'The effect of disintegrin-metalloproteinase ADAM9 in gastric cancer progression', Molecular Cancer Therapeutics, vol. 13, no. 12, pp. 3074-3085. https://doi.org/10.1158/1535-7163.MCT-13-1001

The effect of disintegrin-metalloproteinase ADAM9 in gastric cancer progression. / Kim, Jeong Min; Jeung, Hei Cheul; Rha, Sun Young; Yu, Eun Jeong; Kim, Tae Soo; Shin, You Keun; Zhang, Xianglan; Park, Kyu Hyun; Park, Seung Woo; Chung, Hyun Cheol; Powis, Garth.

In: Molecular Cancer Therapeutics, Vol. 13, No. 12, 01.12.2014, p. 3074-3085.

Research output: Contribution to journalArticle

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AU - Kim, Jeong Min

AU - Jeung, Hei Cheul

AU - Rha, Sun Young

AU - Yu, Eun Jeong

AU - Kim, Tae Soo

AU - Shin, You Keun

AU - Zhang, Xianglan

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AU - Park, Seung Woo

AU - Chung, Hyun Cheol

AU - Powis, Garth

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