Calpain-dependent proteolysis of merlin occurs by oxidative stress in meningiomas: A novel hypothesis of tumorigenesis

Takuro Kaneko, Tetsumori Yamashima, Yasuo Tohma, Motohiro Nomura, Shinobu Imajoh-Ohmi, Takaomi C. Saido, Mitsuyoshi Nakao, Hideyuki Saya, Hiroshi Yamamoto, Junkoh Yamashita

Research output: Contribution to journalArticle

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Abstract

BACKGROUND. The purpose of this study is to indicate that oxidative stress may contribute to occurrence of meningiomas. Recently, it was reported that aside from the neurofibromatosis type 2 (NF2) gene mutations, the calpain-dependent proteolysis of the NF2 gene product, merlin might be closely related to the development of certain NF2-related tumors. Although meningiomas are well known to occur more frequently in aged persons, it still remains unknown why calpain activation occurs predominantly in them. Because the production of free radicals with aging might be one of the causes of calpain activation especially in leptomeningeal cells being devoid of blood supply, the authors examined the relations between μ-calpain activation and merlin proteolysis induced by the oxidative stress. METHODS. The authors examined 12 patient-derived sporadic meningiomas and their primary cultured cells. Malignant glioma cell line (U-251MG), which had no relation to NF2, was used as a control. They were exposed to hydrogen peroxide (H2O2) for 1 hour. After oxidative stress, they were examined by Western blot and immunofluorescence microscopic analyses. RESULTS. Despite the consistent expressions of activated μ-calpain in 11 of 12 meningioma tissues, this calpain activation completely disappeared after culture; instead the full-length merlin appeared again in 8 of 11 cases. The treatment of cultured cells with hydrogen peroxide induced both μ-calpain-dependent cleavage of merlin and reduction of an intrinsic calpain inhibitor calpastatin. Such proteolysis was significantly blocked by a specific calpain inhibitor, Z-LLal. The full-length merlin was immunocytochemically colocalized with activated μ-calpain at the plasma membrane, and, after μ-calpain activation, the fragment of merlin translocated to the perinuclear cytoplasm or into the nucleus. CONCLUSIONS. These findings suggest that oxidative stress-induced activation of μ-calpain causes proteolysis of merlin conceivably to impair cell adhesion and/or contact inhibition of meningioma cells.

Original languageEnglish
Pages (from-to)2662-2672
Number of pages11
JournalCancer
Volume92
Issue number10
DOIs
Publication statusPublished - 2001 Nov 15
Externally publishedYes

Fingerprint

Neurofibromin 2
Calpain
Meningioma
Proteolysis
Carcinogenesis
Oxidative Stress
Neurofibromatosis 2
Hydrogen Peroxide
Cultured Cells
Neurofibromatosis 2 Genes
Contact Inhibition
Cell Adhesion
Glioma
Free Radicals
Fluorescent Antibody Technique
Cytoplasm
Western Blotting

Keywords

  • Calpain
  • Meningioma
  • Merlin
  • Oxidative stress

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Calpain-dependent proteolysis of merlin occurs by oxidative stress in meningiomas : A novel hypothesis of tumorigenesis. / Kaneko, Takuro; Yamashima, Tetsumori; Tohma, Yasuo; Nomura, Motohiro; Imajoh-Ohmi, Shinobu; Saido, Takaomi C.; Nakao, Mitsuyoshi; Saya, Hideyuki; Yamamoto, Hiroshi; Yamashita, Junkoh.

In: Cancer, Vol. 92, No. 10, 15.11.2001, p. 2662-2672.

Research output: Contribution to journalArticle

Kaneko, T, Yamashima, T, Tohma, Y, Nomura, M, Imajoh-Ohmi, S, Saido, TC, Nakao, M, Saya, H, Yamamoto, H & Yamashita, J 2001, 'Calpain-dependent proteolysis of merlin occurs by oxidative stress in meningiomas: A novel hypothesis of tumorigenesis', Cancer, vol. 92, no. 10, pp. 2662-2672. https://doi.org/10.1002/1097-0142(20011115)92:10<2662::AID-CNCR1620>3.0.CO;2-9
Kaneko, Takuro ; Yamashima, Tetsumori ; Tohma, Yasuo ; Nomura, Motohiro ; Imajoh-Ohmi, Shinobu ; Saido, Takaomi C. ; Nakao, Mitsuyoshi ; Saya, Hideyuki ; Yamamoto, Hiroshi ; Yamashita, Junkoh. / Calpain-dependent proteolysis of merlin occurs by oxidative stress in meningiomas : A novel hypothesis of tumorigenesis. In: Cancer. 2001 ; Vol. 92, No. 10. pp. 2662-2672.
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abstract = "BACKGROUND. The purpose of this study is to indicate that oxidative stress may contribute to occurrence of meningiomas. Recently, it was reported that aside from the neurofibromatosis type 2 (NF2) gene mutations, the calpain-dependent proteolysis of the NF2 gene product, merlin might be closely related to the development of certain NF2-related tumors. Although meningiomas are well known to occur more frequently in aged persons, it still remains unknown why calpain activation occurs predominantly in them. Because the production of free radicals with aging might be one of the causes of calpain activation especially in leptomeningeal cells being devoid of blood supply, the authors examined the relations between μ-calpain activation and merlin proteolysis induced by the oxidative stress. METHODS. The authors examined 12 patient-derived sporadic meningiomas and their primary cultured cells. Malignant glioma cell line (U-251MG), which had no relation to NF2, was used as a control. They were exposed to hydrogen peroxide (H2O2) for 1 hour. After oxidative stress, they were examined by Western blot and immunofluorescence microscopic analyses. RESULTS. Despite the consistent expressions of activated μ-calpain in 11 of 12 meningioma tissues, this calpain activation completely disappeared after culture; instead the full-length merlin appeared again in 8 of 11 cases. The treatment of cultured cells with hydrogen peroxide induced both μ-calpain-dependent cleavage of merlin and reduction of an intrinsic calpain inhibitor calpastatin. Such proteolysis was significantly blocked by a specific calpain inhibitor, Z-LLal. The full-length merlin was immunocytochemically colocalized with activated μ-calpain at the plasma membrane, and, after μ-calpain activation, the fragment of merlin translocated to the perinuclear cytoplasm or into the nucleus. CONCLUSIONS. These findings suggest that oxidative stress-induced activation of μ-calpain causes proteolysis of merlin conceivably to impair cell adhesion and/or contact inhibition of meningioma cells.",
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T2 - A novel hypothesis of tumorigenesis

AU - Kaneko, Takuro

AU - Yamashima, Tetsumori

AU - Tohma, Yasuo

AU - Nomura, Motohiro

AU - Imajoh-Ohmi, Shinobu

AU - Saido, Takaomi C.

AU - Nakao, Mitsuyoshi

AU - Saya, Hideyuki

AU - Yamamoto, Hiroshi

AU - Yamashita, Junkoh

PY - 2001/11/15

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N2 - BACKGROUND. The purpose of this study is to indicate that oxidative stress may contribute to occurrence of meningiomas. Recently, it was reported that aside from the neurofibromatosis type 2 (NF2) gene mutations, the calpain-dependent proteolysis of the NF2 gene product, merlin might be closely related to the development of certain NF2-related tumors. Although meningiomas are well known to occur more frequently in aged persons, it still remains unknown why calpain activation occurs predominantly in them. Because the production of free radicals with aging might be one of the causes of calpain activation especially in leptomeningeal cells being devoid of blood supply, the authors examined the relations between μ-calpain activation and merlin proteolysis induced by the oxidative stress. METHODS. The authors examined 12 patient-derived sporadic meningiomas and their primary cultured cells. Malignant glioma cell line (U-251MG), which had no relation to NF2, was used as a control. They were exposed to hydrogen peroxide (H2O2) for 1 hour. After oxidative stress, they were examined by Western blot and immunofluorescence microscopic analyses. RESULTS. Despite the consistent expressions of activated μ-calpain in 11 of 12 meningioma tissues, this calpain activation completely disappeared after culture; instead the full-length merlin appeared again in 8 of 11 cases. The treatment of cultured cells with hydrogen peroxide induced both μ-calpain-dependent cleavage of merlin and reduction of an intrinsic calpain inhibitor calpastatin. Such proteolysis was significantly blocked by a specific calpain inhibitor, Z-LLal. The full-length merlin was immunocytochemically colocalized with activated μ-calpain at the plasma membrane, and, after μ-calpain activation, the fragment of merlin translocated to the perinuclear cytoplasm or into the nucleus. CONCLUSIONS. These findings suggest that oxidative stress-induced activation of μ-calpain causes proteolysis of merlin conceivably to impair cell adhesion and/or contact inhibition of meningioma cells.

AB - BACKGROUND. The purpose of this study is to indicate that oxidative stress may contribute to occurrence of meningiomas. Recently, it was reported that aside from the neurofibromatosis type 2 (NF2) gene mutations, the calpain-dependent proteolysis of the NF2 gene product, merlin might be closely related to the development of certain NF2-related tumors. Although meningiomas are well known to occur more frequently in aged persons, it still remains unknown why calpain activation occurs predominantly in them. Because the production of free radicals with aging might be one of the causes of calpain activation especially in leptomeningeal cells being devoid of blood supply, the authors examined the relations between μ-calpain activation and merlin proteolysis induced by the oxidative stress. METHODS. The authors examined 12 patient-derived sporadic meningiomas and their primary cultured cells. Malignant glioma cell line (U-251MG), which had no relation to NF2, was used as a control. They were exposed to hydrogen peroxide (H2O2) for 1 hour. After oxidative stress, they were examined by Western blot and immunofluorescence microscopic analyses. RESULTS. Despite the consistent expressions of activated μ-calpain in 11 of 12 meningioma tissues, this calpain activation completely disappeared after culture; instead the full-length merlin appeared again in 8 of 11 cases. The treatment of cultured cells with hydrogen peroxide induced both μ-calpain-dependent cleavage of merlin and reduction of an intrinsic calpain inhibitor calpastatin. Such proteolysis was significantly blocked by a specific calpain inhibitor, Z-LLal. The full-length merlin was immunocytochemically colocalized with activated μ-calpain at the plasma membrane, and, after μ-calpain activation, the fragment of merlin translocated to the perinuclear cytoplasm or into the nucleus. CONCLUSIONS. These findings suggest that oxidative stress-induced activation of μ-calpain causes proteolysis of merlin conceivably to impair cell adhesion and/or contact inhibition of meningioma cells.

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