title: GM3 synthase gene is a novel biomarker for histological classification and drug sensitivity against epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer.
abstract: Expression of gangliosides and alterations in their composition have been observed during cell proliferation and differentiation and in certain cell cycle phases, brain development and cancer malignancy. To investigate the characteristics of GM3 synthase, SAT-I mRNA and ganglioside GM3 expression levels in lung cancer, we examined the expression levels of SAT-I mRNA as well as GM3 in 40 tumor tissues surgically removed from non-small cell lung cancer patients. Adenocarcinoma tissues expressed SAT-I mRNA levels that were significantly higher than those of squamous and other carcinomas (P < 0.0001). Moreover, the SAT-I mRNA levels were high in the bronchioalveolar carcinoma subtype and low in the solid and mucin subtypes of adenocarcinomas (P = 0.049, 0.049 and 0.013, respectively). To clarify the relationship between SAT-I mRNA and epidermal growth factor receptor (EGFR)-tyrosine kinase (TK) inhibitor sensitivity, we carried out drug sensitivity tests for the EGFR-TK inhibitors gefitinib and AG1478 using eight adenocarcinoma cell lines expressing no EGFR mutations. The IC(50) values for gefitinib and AG1478 decreased dramatically with increasing SAT-I mRNA levels (R(2) = 0.81 and 0.59, respectively), representing a wide range of drug sensitivities among adenocarcinoma cell lines. To explore a possible mechanism of how GM3 could enhance the sensitivity to EGFR-TK inhibitors, the SAT-I gene was introduced stably into a GM3-negative clone of murine 3LL lung cancer cells to produce GM3-reconstituted clones. We found an increase in EGFR protein levels and gefitinib sensitivity in GM3-reconstituted cells, suggesting the involvement of GM3 in the turnover of EGFR protein. Therefore, it is highly expected that, by measuring the expression levels of SAT-I mRNA in lung biopsy samples from non-small cell lung cancer patients, enhanced pathological identification and individualized chemotherapeutic strategies can be established for the appropriate use of EGFR-TK inhibitors.
authors: Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Hokkaido 060-0812, Japan.
authors: Mariko
authors: M
authors: Noguchi
authors: Tomoko
authors: T
authors: Suzuki
authors: Kazuya
authors: K
authors: Kabayama
authors: Hiroki
authors: H
authors: Takahashi
authors: Hirofumi
authors: H
authors: Chiba
authors: Masanori
authors: M
authors: Shiratori
authors: Shosaku
authors: S
authors: Abe
authors: Atsushi
authors: A
authors: Watanabe
authors: Masaaki
authors: M
authors: Satoh
authors: Tadashi
authors: T
authors: Hasegawa
authors: Seiichi
authors: S
authors: Tagami
authors: Atsushi
authors: A
authors: Ishii
authors: Masaki
authors: M
authors: Saitoh
authors: Masanori
authors: M
authors: Kaneko
authors: Ken
authors: K
authors: Iseki
authors: Yasuyuki
authors: Y
authors: Igarashi
authors: Jin-ichi
authors: J
authors: Inokuchi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005679:G(M3) Ganglioside / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
chemical_list: D005679:G(M3) Ganglioside; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D012799:Sialyltransferases; C021343:haematoside synthetase; D066246:ErbB Receptors; D000077156:Gefitinib
references: Eur J Cancer. 2001 Sep;37 Suppl 4:S9-15
references: 11597399
references: J Biol Chem. 2003 Dec 5;278(49):48770-8
references: 14512423
references: Eur Respir J. 2003 Jul;22(1):179-81
references: 12882469
references: Glycobiology. 2003 Mar;13(3):207-16
references: 12626418
references: Anal Biochem. 1994 Sep;221(2):312-6
references: 7810872
references: Curr Opin Pharmacol. 2005 Aug;5(4):343-9
references: 15950538
references: Clin Cancer Res. 2003 Jun;9(6):2316-26
references: 12796401
references: N Engl J Med. 2004 May 20;350(21):2129-39
references: 15118073
references: Oncogene. 2000 Nov 20;19(49):5548-57
references: 11114734
references: J Biol Chem. 2002 Mar 22;277(12):10108-13
references: 11796728
references: JAMA. 2003 Oct 22;290(16):2149-58
references: 14570950
references: Lung Cancer. 2003 Jun;40(3):339-42
references: 12781434
references: J Clin Oncol. 2003 Jun 15;21(12):2237-46
references: 12748244
references: Eur J Cancer. 2006 Jan;42(1):17-23
references: 16364841
references: Gan To Kagaku Ryoho. 2004 Apr;31(4):567-73
references: 15114701
references: Glycobiology. 2006 Jul;16(7):641-50
references: 16571667
references: Lancet. 2003 Jan 11;361(9352):137-9
references: 12531582
references: J Biol Chem. 1990 Nov 5;265(31):18713-6
references: 2229037
references: J Clin Oncol. 2004 Mar 15;22(6):1103-9
references: 15020612
references: Science. 2004 Jun 4;304(5676):1497-500
references: 15118125
references: CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
references: 15761078
references: J Biol Chem. 2002 Dec 6;277(49):47028-34
references: 12354760
references: Cancer Cell. 2004 May;5(5):411-5
references: 15144948
references: Sci STKE. 2002 Nov 26;2002(160):re15
references: 12454318