Sorting nexin 2-mediated membrane trafficking of c-Met contributes to sensitivity of molecular-targeted drugs

Sayaka Ogi, Hideaki Fujita, Masaki Kashihara, Chizuko Yamamoto, Kahori Sonoda, Isamu Okamoto, Kazuhiko Nakagawa, Shigehiro Ohdo, Yoshitaka Tanaka, Michihiko Kuwano, Mayumi Ono

研究成果: ジャーナルへの寄稿記事

13 引用 (Scopus)

抄録

The sorting nexin (SNX) family is a diverse group of cytoplasmic and membrane-associated proteins that are involved in membrane-trafficking steps within the endocytotic network. SNX1 and SNX2 are components of the mammalian retromer complex and they also play critical roles in the membrane trafficking of growth factor receptors including epidermal growth factor receptor (EGFR) and c-Met. The human lung cancer cell lines, which harbor activating mutations in the kinase domain of EGFR gene, are sensitive to EGFR-targeted drugs gefitinib or erlotinib. However, a lung cancer cell line harboring gene amplification of c-Met is sensitive to the c-Met-targeted drug SU11274 but not to EGFR-targeted drugs. C-Met overexpression is identified as one of the bypass mechanisms for acquired resistance to EGFR-targeted drugs. Here we show that the siRNA-mediated knockdown of SNX2 decreases the cell-surface localization of c-Met, but not that of EGFR, resulting in lysosomal degradation of the c-Met protein. SNX2 specifically interacts with c-Met and treatment with lysosomal inhibitors almost completely annihilates downregulation of c-Met protein by SNX2 knockdown. Therefore, silencing of SNX2 markedly alters sensitivity to anticancer drugs targeted to c-Met (SU11274) and EGFR (gefitinib and erlotinib) through promotion of compensatory activation of the EGFR pathway in lung cancer cells. These findings suggest that development of drugs targeting SNX2 could be useful in overcoming drug resistance to EGFR-targeted drugs in lung cancer cells harboring c-Met gene amplification.

元の言語英語
ページ(範囲)573-583
ページ数11
ジャーナルCancer Science
104
発行部数5
DOI
出版物ステータス出版済み - 5 1 2013

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Sorting Nexins
Epidermal Growth Factor Receptor
Membranes
Pharmaceutical Preparations
Lung Neoplasms
Proto-Oncogene Proteins c-met
Gene Amplification
erbB-1 Genes
Cell Line
Growth Factor Receptors
Drug Delivery Systems
Drug Resistance
Small Interfering RNA
Membrane Proteins
Phosphotransferases
Down-Regulation
Cell Membrane

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

Sorting nexin 2-mediated membrane trafficking of c-Met contributes to sensitivity of molecular-targeted drugs. / Ogi, Sayaka; Fujita, Hideaki; Kashihara, Masaki; Yamamoto, Chizuko; Sonoda, Kahori; Okamoto, Isamu; Nakagawa, Kazuhiko; Ohdo, Shigehiro; Tanaka, Yoshitaka; Kuwano, Michihiko; Ono, Mayumi.

:: Cancer Science, 巻 104, 番号 5, 01.05.2013, p. 573-583.

研究成果: ジャーナルへの寄稿記事

Ogi, S, Fujita, H, Kashihara, M, Yamamoto, C, Sonoda, K, Okamoto, I, Nakagawa, K, Ohdo, S, Tanaka, Y, Kuwano, M & Ono, M 2013, 'Sorting nexin 2-mediated membrane trafficking of c-Met contributes to sensitivity of molecular-targeted drugs', Cancer Science, 巻. 104, 番号 5, pp. 573-583. https://doi.org/10.1111/cas.12117
Ogi, Sayaka ; Fujita, Hideaki ; Kashihara, Masaki ; Yamamoto, Chizuko ; Sonoda, Kahori ; Okamoto, Isamu ; Nakagawa, Kazuhiko ; Ohdo, Shigehiro ; Tanaka, Yoshitaka ; Kuwano, Michihiko ; Ono, Mayumi. / Sorting nexin 2-mediated membrane trafficking of c-Met contributes to sensitivity of molecular-targeted drugs. :: Cancer Science. 2013 ; 巻 104, 番号 5. pp. 573-583.
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AU - Sonoda, Kahori

AU - Okamoto, Isamu

AU - Nakagawa, Kazuhiko

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