RRC ID 58827
Author Yamazaki S, Su Y, Maruyama A, Makinoshima H, Suzuki J, Tsuboi M, Goto K, Ochiai A, Ishii G.
Title Uptake of collagen type I via macropinocytosis cause mTOR activation and anti-cancer drug resistance.
Journal Biochem Biophys Res Commun
Abstract Collagen type I (Col I) is one of the major extracellular matrix proteins in the cancer tissue. Previously, we have reported that Col I induces epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance by mTOR activation through Akt and ERK1/2 independent pathway. In this study, we aimed to elucidate the molecular mechanism of Col I induced EGFR-TKI resistance. First, we demonstrated the uptake of fluorescently labeled Col I by EGFR-mutated lung cancer cell line PC-9 cells using confocal microscopy and flow cytometry. Metabolome analysis revealed that the metabolic profiles of PC-9 cells was influenced by Col I treatment. Uptake of Col I into PC-9 cells was not inhibited by MMP inhibitor, GM6001, and endocytosis inhibitors, Pitstop2 and Dyngo4a; however, macropinocytosis inhibitor EIPA prevented its uptake. Moreover, the combination of EIPA and EGFR-TKI abrogated Col I-induced EGFR-TKI resistance in PC-9 cells. Inhibition of Rac1, which is essential for micropinocytosis, also decreased the uptake of Col I in PC-9 cells and restored their sensitivity to EGFR-TKI. Thus, EGFR mutated lung cancer cells could develop EGFR-TKI resistance by Col I uptake by macropinocytosis route.
Volume 526(1)
Pages 191-198
Published 2020-5-21
DOI 10.1016/j.bbrc.2020.03.067
PII S0006-291X(20)30552-0
PMID 32201076
MeSH Amino Acids / metabolism Antineoplastic Agents / pharmacology* Cell Line, Tumor Collagen Type I / metabolism* Cytoplasm / drug effects Cytoplasm / metabolism Drug Resistance, Neoplasm* / drug effects ErbB Receptors / metabolism Gefitinib / pharmacology Humans Mechanistic Target of Rapamycin Complex 1 / metabolism Metabolomics Pinocytosis* / drug effects Protein Kinase Inhibitors / pharmacology TOR Serine-Threonine Kinases / metabolism* rac1 GTP-Binding Protein / metabolism
IF 2.985
Times Cited 0
Human and Animal Cells TE-10(RCB2099)