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.