Identification of semaphorin E as a non-MDR drug resistance gene of human cancers

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 cisdiamminedichloroplatinum(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.

Biological Activity of Soluble CD100. II. Soluble CD100, Similarly to H-SemaIII, Inhibits Immune Cell Migration

“…In the initial phase they could prevent APCs to infiltrate tumors or to migrate to the locoregional lymph node, while at a later stage they could prevent the metastasis of the malignant cells. Human SemaE is involved in non-multiple drug resistance of human cancers in vitro and in vivo (44). Finally, the semaphorins might control the transmigration of leukocytes from blood to inflammation sites.…”

The brain within the tumor: new roles for axon guidance molecules in cancers

“…SEMA3C was the first secreted semaphorin proposed to be involved in tumorigenesis. 26 A screen for genes responsible for non-MDR (multidrug resistance) drug resistance in human ovarian cancer cell line (TyKnuR) and lung cancer cell line (Lu65/CDDP and MS-1/CDDP) identified SEMA3C as a gene overexpressed in these cells. Several glioma cell lines also express SEMA3C, neuropilins and plexin-As.…”

Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF 165 antagonizes this effect

“…Although the major role of SEMA3 proteins is to guide axons, they are also involved in diverse processes such as immune modulation (9, 10), organogenesis (11), neuronal apoptosis (12), and drug resistance (2,13). SEMA3 members form complexes with two types of cell surface receptors: neuropilins (NP-1 and NP-2) and plexins (14)(15)(16).…”