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RhoGDIβ lacking the N-terminal regulatory domain suppresses metastasis by promoting anoikis in v-src-transformed cells

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Abstract

Rho guanine nucleotide dissociation inhibitors (RhoGDIs) regulate the activity of Rho family GTPases. RhoGDIβ (LyGDI/GDID4/RhoGDI2) has two caspase cleavage sites after Asp19 and Asp55. The resulting cleavage products, ΔN(1–19)RhoGDIβ and ΔN(1–55)RhoGDIβ, are expressed in cells under conditions that activate caspases. ΔN(1–19)RhoGDIβ, which can inhibit GDP dissociation, is implicated in the process of apoptosis, whereas the physiological roles for ΔN(1–55)RhoGDIβ, which lacks the ability to inhibit GDP dissociation, are largely unknown. To explore the roles of ΔN(1–55)RhoGDIβ, we examined the phenotypes of v-src-transformed metastatic fibroblasts transfected with plasmids for expressing ΔN(1–55)RhoGDIβ. Although the expression of ΔN(1–55)RhoGDIβ had no effect on the rate of growth in vitro, it suppressed experimental metastasis and decreased the rate of growth in vivo. In addition, ΔN(1–55)RhoGDIβ-expressing cells had enhanced adhesion to fibronectin, laminin, and collagens but reduced retention in the lung after intravenous injection. Also, the expression of ΔN(1–55)RhoGDIβ promoted anoikis without affecting the levels of activated Rac1 or Cdc42. Furthermore, ΔN(1–55)RhoGDIβ did not affect the expression or phosphorylation of focal adhesion kinase, p44/p42 mitogen-activated protein kinases, or Akt1 before or after induction of anoikis. Thus, ΔN(1–55)RhoGDIβ appears to promote anoikis by undefined mechanisms, thereby suppressing metastasis in v-src-transformed fibroblasts.

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Abbreviations

BSA:

Bovine serum albumin

EMEM:

Eagle’s minimum essential medium

ECM:

Extracellular matrix

FAK:

Focal adhesion kinase

FBS:

Fetal bovine serum

HBSS:

Hanks’ balanced salt solution

MAPK:

Mitogen-activated protein kinase

PAK1:

p21/Cdc42/Rac1-activated kinase 1

PBS:

Phosphate-buffered saline

RhoGDI:

Rho guanine nucleotide dissociation inhibitor

RhoGEF:

Rho guanine nucleotide exchange factor

SDS:

Sodium dodecyl sulfate

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Acknowledgments

This research was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, by the Nature Science Foundation of China (30570548), Project Research from High Technology Center (H2006-8), Grant for Collaborative Research (C2005-2) of Kanazawa Medical University, the Science Research Promotion Fund of The Promotion and Mutual Aid Corporation for Private Schools of Japan, and by the Two Cell Co. Ltd.

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Authors and Affiliations

  1. Division of Molecular Oncology and Virology, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa, 920-0293, Japan

    Takahide Ota, Manabu Murakami & Tsutomu Takegami

  2. Department of Chemistry, Kanazawa Medical University, Uchinada, Ishikawa, 920-0293, Japan

    Masayo Maeda

  3. Department of Regulatory Radiobiology, Research Institute for Radiation Biology and Medicine, Hiroshima , 734-8553, Japan

    Shiho Sakita-Suto & Masaaki Tatsuka

  4. School of Radiation Medicine and Public Health, Suzhou University, Jiang Su, 215007, China

    Xinwen Zhou

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  1. Takahide Ota
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  4. Xinwen Zhou
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Correspondence to Takahide Ota.

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Ota, T., Maeda, M., Sakita-Suto, S. et al. RhoGDIβ lacking the N-terminal regulatory domain suppresses metastasis by promoting anoikis in v-src-transformed cells. Clin Exp Metastasis 23, 323–334 (2006). https://doi.org/10.1007/s10585-006-9041-y

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