Disease relevance of DPH1

• Expression of OVCA1, a candidate tumor suppressor, is reduced in tumors and inhibits growth of ovarian cancer cells [1].
• Attempts to create cell lines that stably expressed OVCA1 from the cytomegalovirus promoter were generally unsuccessful in a variety of different cell lines [1].
• Loss of OVCA1/DPH2L1 correlates with ovarian and breast cancer [2].
• Via this mechanism, tumor cell types that do not express MMPs (such as OVCA 432) nevertheless may be able to utilize exogenous MMP-2 to mediate proteolysis associated with invasion and metastasis [3].
• Using density gradient centrifugation, we isolated the plasma membrane fractions of two ovarian adenocarcinoma cell lines, DOV 13 and OVCA' 432, previously described either to express MMP-2 or to express no gelatinolytic metalloproteinases, respectively [3].

High impact information on DPH1

• The close linkage of OVCA1 and p53 on human Chromosome 17 suggests that coordinated loss may be an important mechanism for the evolution of ovarian, breast, and other tumor phenotypes [2].
• When alkylating agents and toxin conjugates were used in combination, the addition of the immunotoxins to cisplatin, or to cisplatin and thiotepa, produced synergistic cytotoxic activity against the OVCA 432 and OVCAR III cell lines [4].
• OVCA1, also known as DPH2L1, is a tumor suppressor gene associated with ovarian carcinoma and other tumors [5].
• The human tumor suppressor gene OVCA1, previously identified as homologous to yeast DPH2, is shown to actually be HsDPH1 [6].
• ELISA, gelatin zymography, Western blot, and reverse transcription-PCR analyses demonstrated that in two ovarian carcinoma cell lines (HEY and OVCA 433), the expression of matrix metalloproteinase (MMP) -2, -9, -3, -7, and -13 was up-regulated and activated by ET-1 [7].

Chemical compound and disease context of DPH1

• Previous studies from our laboratory have demonstrated that OVCA 433 human ovarian carcinoma cells are glucocorticoid responsive by several criteria and contain high affinity, saturable, steroid-specific glucocorticoid receptors [8].
• We investigated the effect of the flavonoid quercetin (Q) on the proliferation of the ovarian cancer cell line OVCA 433 [9].
• Silybin, used in concentrations from 0.1 to 20 microM, exerted a dose-dependent growth inhibitory effect on OVCA 433, A2780 parental and drug-resistant ovarian cancer cells, and MCF-7 doxorubicin (DOX)-resistant breast cancer cells (IC50 = 4.8-24 microM) [10].
• Effects of dexamethasone on the growth and epidermal growth factor receptor expression of the OVCA 433 ovarian cancer cells [11].
• In conclusion, neither Es, Pr, nor Dex regulates HER-2/neu mRNA levels in NIH:OVCAR-3, SW 626, OVCA 433, and Caov-3 ovarian cancer cells [12].

Biological context of DPH1

• The OVCA1 gene is a candidate for the breast and ovarian tumor suppressor gene at chromosome 17p13 [13].
• OVCA1 is a candidate tumor suppressor gene mapping to a highly conserved region on chromosome 17p13.3 that shows frequent loss of heterozygosity in breast and ovarian carcinomas [1].
• These results suggest that slight alterations in the level of OVCA1, such as would occur after reduction of chromosome 17p13.13 to hemizygosity, may result in cell cycle deregulation and promote tumorigenesis [1].
• This reduction of colony formation was quantified in the ovarian cancer cell line A2780, where it was demonstrated that cells transfected with plasmids expressing OVCA1 had a 50-60% reduction in colony number as compared with appropriate controls, and only a few of these clones expressed OVCA1, albeit at low levels [1].
• Mouse Ovca1 contains at least 13 exons and spans approximately 17 kb [14].

Anatomical context of DPH1

• Western blot analysis of extracts prepared from breast and ovarian carcinomas revealed reduced expression of OVCA1 compared with extracts from normal epithelial cells from these tissues [1].
• The buoyant densities of the CA 125 antigen complexes from human serum, OVCA 433 cells, and human milk were in the range of 1.36 to 1.46 g/ml [15].
• Finally, conditioned media from OVCA 433 as well as ascitic fluids caused an increase in endothelial cell migration and the ET-1 receptor blockade significantly inhibited this angiogenic response [16].
• Upon EGF receptor activation, DOV 13, OVEA6 and OVCA 429 cells were induced to invade through an artificial basement membrane (Matrigel); however, no invasion was detected in OVCA 432 cells [17].
• Inhibitory effect of quercetin on OVCA 433 cells and presence of type II oestrogen binding sites in primary ovarian tumours and cultured cells [9].

Associations of DPH1 with chemical compounds

• Our results are in contrast to a previous report and show that OVCA2, not OVCA1 mRNA and protein, is downregulated in response to RA and 4HPR [18].
• Previous work has shown that OVCA 433 cells are growth inhibited by glucocorticoids and contain 14,000 glucocorticoid receptors per cell with an affinity for dexamethasone (Kd = 6.6 x 10(-9) M) which corresponds well with the concentration required for half-maximal CA125 inhibition [19].
• One OCa cell line, OVCA 433, was found to be nonresponsive to androgen stimulation [20].
• Here we show that release of CA125 by OVCA 433 cells is 90 to 95% inhibited by treatment with 1 x 10(-7) M dexamethasone, as determined using a biotin-based enzyme-linked immunosorbent assay utilizing OC125 monoclonal antibodies to CA125 [19].
• Gene trap mutagenesis-based forward genetic approach reveals that the tumor suppressor OVCA1 is a component of the biosynthetic pathway of diphthamide on elongation factor 2 [21].

Other interactions of DPH1

• Using allelic loss mapping and positional cloning methods, we have recently identified two novel genes, which we refer to as OVCA1 and OVCA2, that map to 17p13 [22].
• Candidate genes within this region are HIC-1, a potential tumour-suppressor gene, and DPH2L, a gene that has been cloned from the ovarian critical region [23].
• We have identified a cDNA corresponding to the sequence of the known gene diphthamide biosynthesis protein 2-like (DPH2L) [24].

Analytical, diagnostic and therapeutic context of DPH1

• Northern blot analysis reveals that OVCA1 and OVCA2 mRNA were expressed in normal surface epithelial cells of the ovary, but the level of this transcript is significantly reduced or is undetectable in 92% (11/12) of the ovarian tumors and tumor cell lines analyzed [22].
• Western blot and immunohistochemistry revealed that mouse OVCA1 is a 50-kDa protein that is predominately localized in a punctate pattern in the nucleus [14].
• The exposure of HOSE or OVCA cell cultures to 10(-6) M P4 induced time-dependent increases in early and late apoptotic cells and activation of caspase-8 and -3, but not that of caspase-9 [25].
• In this report, we provide evidence that DPH2L is down-regulated during differentiation or apoptosis in several cancer cell lines after treatment with all-trans RA or N-(4-hydroxyphenyl)retinamide and during cell-cycle arrest [24].
• To begin to assess the role of PTPs in ovarian cancer cell growth regulation, PTP partial cDNAs were cloned from the OVCA 433 ovarian cancer cell line using RT/PCR and degenerate oligonucleotide primers for the PTP consensus domain [26].

References