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Identification of semaphorin E as a non-MDR drug resistance gene of human cancers
1Pathology Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104, Japan.
Abstract:
To improve cancer chemotherapy, a better understanding of the molecular mechanisms of drug resistance is essential. To identify the molecules responsible for drug resistance that is unrelated to MDR1 or MRP gene products, a eukaryotic expression cDNA library of cis-diamminedichloroplatinum(II) (CDDP)-resistant ovarian cancer TYKnuR cells was introduced into Cos-7 cells. After repeated CDDP selection, cDNA homologous to murine semaphorin E was isolated from surviving cells. Human semaphorin E (H-sema E) was overexpressed in CDDP-resistant cell lines and was readily induced not only by diverse chemotherapeutic drugs but also by x-ray and UV irradiation. Transfection of H-sema E conferred a drug-resistant phenotype to CDDP-sensitive cells. In addition, the aberrant expression of H-sema E protein was detected immunohistochemically in 14 of 42 (33.3%) recurrent squamous cell carcinomas removed at autopsy after extensive radiochemotherapy. Recently, another member of the semaphorin family, CD100, was shown to significantly improve the viability of B lymphocytes. These results suggest the involvement of semaphorins in diverse cell survival mechanisms.
Insights
Understanding drug resistance in cancer chemotherapy is crucial. This study identifies human semaphorin E (H-sema E) as a key molecule involved in resistance to chemotherapy and radiation, suggesting semaphorins play a role in cell survival.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Improving cancer chemotherapy requires understanding drug resistance mechanisms.
- Identifying novel molecules involved in drug resistance beyond known gene products (MDR1, MRP) is essential.
Purpose of the Study:
- To identify novel molecular mediators of drug resistance in ovarian cancer.
- To investigate the role of semaphorins in cellular resistance to chemotherapy and irradiation.
Main Methods:
- Construction and screening of a eukaryotic expression cDNA library from cis-diamminedichloroplatinum(II) (CDDP)-resistant ovarian cancer cells (TYKnuR).
- Transfection of identified cDNA into drug-sensitive cells to assess conferred resistance.
- Immunohistochemical analysis of H-sema E expression in recurrent squamous cell carcinomas.
Main Results:
- Isolation of a cDNA homologous to murine semaphorin E from CDDP-resistant cells.
- Overexpression of human semaphorin E (H-sema E) in CDDP-resistant cell lines, induced by various chemotherapeutic drugs and irradiation.
- Transfection of H-sema E conferred resistance to CDDP in sensitive cells.
- Aberrant H-sema E protein expression observed in 33.3% of recurrent squamous cell carcinomas.
Conclusions:
- Human semaphorin E (H-sema E) is implicated in resistance to chemotherapy and radiation therapy.
- Semaphorins may play a significant role in diverse cellular survival mechanisms, including cancer drug resistance.