Purpose: The cytochromes P450 are a multigene family of enzymes with a central role in the oxidative metabolism of a wide range of xenobiotics, including anticancer drugs and biologically active endogenous compounds. The purpose of this study was to define the cytochrome P450 profile of ovarian cancer and identify novel therapeutic targets and establish the prognostic significance of expression of individual cytochrome P450s in this type of cancer. Experimental Design: Immunohistochemistry for a panel of 23 cytochrome P450s and cytochrome P450 reductase was done on an ovarian cancer tissue microarray consisting of 99 primary epithelial ovarian cancers, 22 peritoneal metastasis, and 13 normal ovarian samples. The intensity of immunoreactivity in each sample was established by light microscopy. Results: In primary ovarian cancer, several P450s (CYP1B1, CYP2A/2B, CYP2F1, CYP2R1, CYP2U1, CYP3A5, CYP3A7, CYP3A43, CYP4Z1, CYP26A1, and CYP51) were present at a significantly higher level of intensity compared with normal ovary. P450 expression was also detected in ovarian cancer metastasis and CYP2S1 and P450 reductase both showed significantly increased expression in metastasis compared with primary ovarian cancer. The presence of low/ negative CYP2A/2B (log rank = 7.06, P = 0.008) or positive CYP4Z1 (log rank = 6.19, P = 0.01) immunoreactivity in primary ovarian cancer were each associated with poor prognosis. Both CYP2A/2B and CYP4Z1were also independent markers of prognosis. Conclusions: The expression profile of individual P450s has been established in ovarian cancer. Several P450s show increased expression in ovarian cancer and this provides the basis for developing P450-based therapeutics in ovarian cancer. Expression of CYP2A/2B or CYP4Z1in primary ovarian cancer were independent markers of prognosis.Ovarian cancer is the most common gynecological malignancy worldwide; yet, the 5-year survival rate for this disease has remained low at f30% for the last 20 years and with relatively little recent improvement (1, 2). Poor prognosis is generally considered to be the result of late presentation when ovarian cancer is of advanced stage and the unpredictable and generally very limited response of this type of cancer to current cancer therapies (3, 4). Improved survival in ovarian cancer is, therefore, dependent on the development of new paradigms in treatment.The cytochrome P450 (P450) enzymes are a large family of constitutive and inducible mono-oxygenase enzymes that metabolize many lipophilic, biologically active endogenous and xenobiotic substrates, including a large number of therapeutic drugs and toxic environmental chemicals (5 -8). Currently, the human P450 superfamily is classified into 18 distinct families based on nucleic acid homology (5). Some P450s, especially the major xenobiotic metabolizing forms of P450, have been very well characterized, whereas very little is known about the biology of some of the more recently identified P450s. Individual P450s show characteristic cell type -and tissue-spe...
The protein hPot1 shares homology with telomere-binding proteins in lower eukaryotes and associates with single-stranded telomeric DNA in vitro as well as colocalizing with telomere-binding proteins in vivo. We now show that hPot1 is coimmunoprecipitated with telomeric DNA and that stable expression of this protein in telomerase-positive cells results in telomere elongation, supporting the idea that hPot1 is a bona fide mammalian telomere-binding protein. We previously found that mutations in the N-terminal DAT domain of the hTERT catalytic subunit of telomerase rendered the enzyme catalytically active but unable to elongate telomeres in vivo. This phenotype could be partially rescued by fusion with the double-stranded telomeric protein hTRF2. Given that hPot1 binds to single-stranded DNA in vitro (at the same site that hTERT binds to in vivo), we addressed whether fusion of hPot1 can rescue the DAT mutations more efficiently than that of hTRF2. We now report that a DAT mutant of hTERT is indeed efficiently rescued upon fusion to hPot1. However, this rescue depended on the ability of hPot1 to localize to telomeres rather than binding to DNA per se. These data support a model whereby the DAT domain of hTERT is implicated in telomere-telomerase associations.Telomeres are essential DNA-protein structures that cap and protect the ends of eukaryotic chromosome from illegitimate recombination, degradation, and detection as DNA damage (10). In humans, the telomere is composed of hundreds to thousands of tandem repeats of the G-rich sequence 5Ј-TTA GGG-3Ј (whereby the G strand overhangs the complementary C strand) and has been proposed to loop around, forming a T loop, and invade the duplex DNA to form a higher-order structure termed the D loop (25). The replication of telomeres poses a unique problem to eukaryotes, as removal of the terminal RNA primer during semiconservative replication of the leading strand leaves a gap that cannot be replicated by known DNA polymerases. In most eukaryotes, this is overcome by the de novo addition of telomeric DNA via the enzyme telomerase (9). Human telomerase is minimally composed of a reversetranscriptase subunit (hTERT) that copies a template region of the accompanying RNA subunit (hTR) onto telomeres as DNA (34). Little is known regarding the mechanism by which the enzyme recognizes telomeres in vivo in higher eukaryotes. However, mutations to either the large N-terminal or smaller C-terminal DAT domains of hTERT render the enzyme catalytically active in vitro but unable to elongate telomeres or extend the life span of telomerase-negative cells in vivo (1, 3). Targeting N-terminal DAT mutants to telomeres by fusion to the double-stranded telomeric DNA-binding protein hTRF2 can extend the life span of telomerase-negative cells, although the growth of these cells was noticeably retarded (2). These results suggest that the DAT domain is involved in telomeretelomerase associations, although this model would be significantly strengthened if it could be demonstrated that a DAT mutant ...
Rhabdomyosarcoma, a malignancy showing features of skeletal muscle differentiation, is the most common soft tissue sarcoma of childhood. The identification of distinct clinical presentation patterns, histologic tumor types, and risk groups suggests that rhabdomyosarcoma is a collection of highly related sarcomas rather than a single entity. In an effort to understand this seemingly heterogeneous malignancy, we constructed a genetically defined but malleable model of rhabdomyosarcoma by converting less differentiated human skeletal muscle cell precursors (SkMC) and committed human skeletal muscle myoblasts (HSMM) into their malignant counterparts by targeting pathways altered in rhabdomyosarcoma. Whereas the two cell types were both tumorigenic, SkMCs gave rise to highly heterogeneous tumors occasionally displaying features of rhabdomyosarcoma, whereas HSMMs formed rhabdomyosarcoma-like tumors with an embryonal morphology, capable of invasion and metastasis. Thus, despite introducing the same panel of genetic changes, altering the skeletal muscle cell of origin led to different tumor morphologies, suggesting that cell of origin may dictate rhabdomyosarcoma tumor histology. The ability to now genetically induce human rhabdomyosarcoma-like tumors provides a representative model to dissect the molecular mechanisms underlying this cancer. (Cancer Res 2005; 65(11): 4490-5)
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