Open AccessSorting nexin 2‐mediated membrane trafficking of c‐ M et contributes to sensitivity of molecular‐targeted drugs
Author(s) -
Ogi Sayaka,
Fujita Hideaki,
Kashihara Masaki,
Yamamoto Chizuko,
Sonoda Kahori,
Okamoto Isamu,
Nakagawa Kazuhiko,
Ohdo Shigehiro,
Tanaka Yoshitaka,
Kuwano Michihiko,
Ono Mayumi
Publication year - 2013
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12117
Subject(s) - gefitinib , erlotinib , epidermal growth factor receptor , cancer research , pleiotrophin , gene knockdown , gene silencing , downregulation and upregulation , small interfering rna , biology , sorting nexin , microbiology and biotechnology , cancer , cell culture , receptor , endosome , growth factor , gene , transfection , genetics , intracellular
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. SNX 1 and SNX 2 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 SU 11274 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 si RNA ‐mediated knockdown of SNX 2 decreases the cell‐surface localization of c‐Met, but not that of EGFR , resulting in lysosomal degradation of the c‐Met protein. SNX 2 specifically interacts with c‐Met and treatment with lysosomal inhibitors almost completely annihilates downregulation of c‐Met protein by SNX 2 knockdown. Therefore, silencing of SNX 2 markedly alters sensitivity to anticancer drugs targeted to c‐Met ( SU 11274) 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 SNX 2 could be useful in overcoming drug resistance to EGFR ‐targeted drugs in lung cancer cells harboring c‐Met gene amplification.