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. (Cancer Sci 2007; 98: 1625-1632) L ung cancer is currently the most frequently diagnosed major cancer worldwide.(1) The WHO classification of lung cancer identifies four major types: squamous cell carcinoma, adenocarcinoma, large cell carcinoma and small cell carcinoma. These tumors are commonly divided into small cell lung cancer and NSCLC based on differences in their biology and treatment. The low cure rate for NSCLC can be attributed to a high rate of metastasis at diagnosis and a lack of effective therapeutics to cure such metastatic disease.

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

“…Sphingosine kinase is important for 1) revascularization responses, 2) regulating the maturation of vascular endothelial progenitors, and 3) controlling cellular recruitment (15,85,89). The cellular balance of the level of Cer, SPH, and S1P, termed the "sphingolipid rheostat," dictates cell fate, whereby Cer and SPH enhance apoptosis while the S1P promotes cell survival and proliferation (16,125,129). However, the actual sphingolipid rheostat may be broad, comprising numerous additional molecules in the SL metabolic map as well as those in related metabolic pathways.…”

“…GM3 impairs glucose uptake via suppression of insulin-stimulated tyrosine phosphorylation of the insulin receptor (125,166,170). GM3 displaces the insulin receptor in lipid rafts, decreasing insulin receptor-dependent signaling (126,129,133).…”

“…Insulin-mediated glucose uptake is altered in GD patients, while non-insulin-mediated glucose uptake during euglycemia and hyperglycemia was not distinguished between GD patients and control subjects. Suppression of lipolysis by insulin was less effective in GD (95,99,129). Insulin resistance in GD is not associated with obesity (131,171,175).…”

“…The loss of insulin receptor from lipid rafts is due to the accumulation of GM3 (81,85,134). Complex GSLs, such as ganglioside GM3, surround the insulin receptor in the raft membrane compartment and modulate signaling through this receptor (95,99,129). GM3 concentrations, for which GC is the precursor, are elevated in plasma and several cell types in GD (58, 62, 128).…”

Assessment of the Molecular Expression and Structure of Gangliosides in Brain Metastasis of Lung Adenocarcinoma by an Advanced Approach Based on Fully Automated Chip-Nanoelectrospray Mass Spectrometry

“…From all lung cancers, non-small cell lung cancer has been shown to exhibit a higher expression levels of GM3 as well as GM3 synthase (sialyltransferase-I or SAT-I) mRNA with a positive correlation between expression levels of SAT-I mRNA and GM3 in tumor tissues [24]. Additionally, overexpression of GM3 synthase was used to determine the effects of endogenous gangliosides on the metastatic process of 3LL Lewis lung carcinoma cells [25].…”