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.
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.
Noguchi
Mariko
M
Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Hokkaido 060-0812, Japan.
Suzuki
Tomoko
T
Kabayama
Kazuya
K
Takahashi
Hiroki
H
Chiba
Hirofumi
H
Shiratori
Masanori
M
Abe
Shosaku
S
Watanabe
Atsushi
A
Satoh
Masaaki
M
Hasegawa
Tadashi
T
Tagami
Seiichi
S
Ishii
Atsushi
A
Saitoh
Masaki
M
Kaneko
Masanori
M
Iseki
Ken
K
Igarashi
Yasuyuki
Y
Inokuchi
Jin-ichi
J
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
D005679:G(M3) Ganglioside; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D012799:Sialyltransferases; C021343:haematoside synthetase; D066246:ErbB Receptors; D000077156:Gefitinib
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