ABSTRACT
Сancer-testis antigens (CTAs) comprise proteins which are aberrantly expressed in various malignancies, yet under normal situation are restricted to only germ cells. Semenogelins 1 and 2 (SEMG1 and 2, respectively) belong to the family of non-X-linked (autosomal) cancer-testis antigens. They are the major protein ingredients of human semen and share 78% of similarity between them on the gene level. SEMG1/2 gene products regulate the motility and fertility of sperm, as well as provide sperm the antibacterial defense. Besides, SEMG1 and SEMG2 were detected in various malignancies including small cell lung cancer (SCLC). However, the biological role of both SEMG1 and 2 proteins in tumorigenesis has not been fully understood. We demonstrate here that SEMG1 and SEMG2 (SEMGs) exhibit different patterns of expression and sub-cellular localization in non-small cell lung cancer (NSCLC) cell lines. To elucidate the biological properties of SEMGs in NSCLC, we established H1299 cell lines that were stably transduced with either SEMGs-overexpressing or knockdown vectors, respectively. Using fluorescence-based dihydroethidium (DHE) assay we showed that both SEMGs augmented the production of reactive oxygen species (ROS) up to 2 times. Moreover, SEMGs (especially SEMG1) strongly increased the number of Annexin V-positive apoptotic cells manifesting an increased sensitivity to genotoxic drugs including doxorubicin, etoposide, and cisplatin. Taken our results together, SEMGs may arguably play a positive role in tumorigenesis by sensitizing NSCLCs to genotoxic therapy.
ABSTRACT
The steroid hormone progesterone is known to have profound effects on growth and differentiation of normal and malignant breast epithelial cells. The biologic actions of progesterone are exerted through the nuclear progesterone receptor-mediated control of target gene transcription. We utilized differential display polymerase chain reaction (DD-RT-PCR) to identify genes whose expression is altered in response to progestins in cultured breast cancer cells. Here we report identification of a gene encoding a member of the MAGUK protein family, hDlg5 (also known as KIAA0583 and P-dlg), as being the primary progestin target gene in MCF-7 breast cancer cells. Quantitative real-time RT-PCR analysis showed a rapid and strong upregulation of hDlg5 mRNA in cells treated with synthetic progestin medroxyprogesterone acetate (MPA) in the presence of estrogen in MCF-7, T47D and ZR-75-1 cells. The induction was abrogated by antiprogestin RU486. hDlg5 mRNA was also upregulated by progesterone, R5020 and dexamethasone. Protein synthesis inhibitor cycloheximide failed to block progestin-mediated induction of the hDlg5 gene. hDlg5 is a member of the growing family of MAGUKs (membrane-associated guanylate kinase homologs) and is to our knowledge the first member of the family reported to be hormonally regulated. hDlg5 is one of the human homologs of the Drosophila gene dlg [lethal(1)discs-large], which was initially identified as a tumor suppressor gene. The Dlg has a well-established role in cell growth control and maintenance of cell adhesion and cell polarity. Domain profile analysis revealed that hDlg5 has 2 additional PDZ domains than previously reported.
