Amino acid starvation culture condition sensitizes EGFR-expressing cancer cell lines to gefitinib-mediated cytotoxicity by inducing atypical necroptosis

International Journal of Oncology
Yu SaitoKeisuke Miyazawa

Abstract

The maintenance of the intracellular level of amino acids is crucial for cellular homeostasis. This is carried out via the regulation of both the influx from the extracellular environment and the recycling of intracellular resources. Since epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors, including gefitinib (GEF) have been reported to induce the apoptosis of several cancer cell lines, in the present study, we examined whether the cytotoxic effects of GEF are further enhanced under amino acid starvation (AAS) culture conditions. Under AAS culture conditions, the cell killing effect of GEF was synergistically pronounced in the EGFR-expressing cell lines, namely, CAL 27, Detroit 562, A549 and PANC-1 cells compared with those treated with either GEF or AAS alone. The addition of essential amino acids, but not non-essential amino acids to the cell culture medium resulted in the cancellation of this pronounced cytotoxicity. The knockdown of L-type amino acid transporter 1 (LAT-1) by siRNA also enhanced GEF-induced cytotoxicity. Therefore, the shortage of the intracellular amino acid pool appears to determine the sensitivity to GEF. Notably, this enhanced cytotoxicity is not mediated by the induction of apoptosis, b...Continue Reading

References

Feb 13, 1999·The Journal of Biological Chemistry·X M SunG M Cohen
Jul 31, 2004·Science·Raffaella SordellaJeffrey Settleman
Nov 24, 2004·Nature Cell Biology·Shigeomi ShimizuYoshihide Tsujimoto
Sep 9, 2005·Nature Reviews. Cancer·Yasuko KondoSeiji Kondo
Sep 13, 2005·Bioorganic & Medicinal Chemistry Letters·Xin TengGregory D Cuny
Jan 13, 2006·Nature Chemical Biology·Alexei DegterevJunying Yuan
Feb 29, 2008·Nature·Noboru MizushimaDaniel J Klionsky
Mar 14, 2008·The New England Journal of Medicine·Fortunato Ciardiello, Giampaolo Tortora
Apr 15, 2008·Nature Chemical Biology·Alexei DegterevJunying Yuan
Nov 11, 2009·Cancer Science·Koji OdaHitoshi Endou
Mar 13, 2010·Seminars in Cell & Developmental Biology·Akiko Kuma, Noboru Mizushima
Apr 29, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Akihiko KawaharaMayumi Ono
Jan 25, 2011·Nature Cell Biology·Joungmok KimKun-Liang Guan
Jun 4, 2011·BMC Biology·Tom Egil Hansen, Terje Johansen
Apr 27, 2012·Nature Reviews. Cancer·Eileen White
Sep 8, 2012·Cancer Biology & Therapy·Christopher FungUmamaheswar Duvvuri
Jul 3, 2013·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Junqing WangZhenggang Zhu
Dec 7, 2014·Cell·Lorenzo GalluzziGuido Kroemer
Jan 17, 2015·Cell·Xiaojun TanRichard A Anderson
Feb 6, 2015·The Journal of Clinical Investigation·Young Chul Kim, Kun-Liang Guan
Feb 20, 2015·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Eiki IchiharaKatsuyuki Kiura
May 25, 2016·Developmental Cell·Megan L GoodallAndrew Thorburn
Sep 16, 2016·Apoptosis : an International Journal on Programmed Cell Death·Lei ChenYifa Zhou
Nov 22, 2016·Nature Communications·Piero Dalle PezzeKathrin Thedieck
Dec 7, 2016·Molecular and Cellular Biology·Deli HuangJiahuai Han
Dec 22, 2016·Nature Reviews. Molecular Cell Biology·Ricardo WeinlichDouglas R Green

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Citations

Aug 17, 2019·International Journal of Molecular Sciences·Yi-Ta HsiehWan-Chun Li

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Methods Mentioned

BETA
flow cytometry
electrophoresis
transfection
immunoprecipitation assay

Software Mentioned

ZEN

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