Obstacles to the expansion of cells with proliferative potential include the induction of cell death, telomerebased senescence, and the pRb and p53 tumor suppressors. Not infrequently, the molecular pathways regulating oncogenesis recapitulate aberrations of processes governing embryogenesis. The genetic network, consisting of the dachshund (dac), eyes absent (eya), eyeless, and sine oculis (so) genes, regulates cell fate determination in metazoans, with dac serving as a cointegrator through a So DNA-binding factor. Here, DACH1 inhibited oncogene-mediated breast oncogenesis, blocking breast cancer epithelial cell DNA synthesis, colony formation, growth in Matrigel, and tumor growth in mice. Genetic deletion studies demonstrated a requirement for cyclin D1 in DACH1-mediated inhibition of DNA synthesis. DACH1 repressed cyclin D1 through a novel mechanism via a c-Jun DNA-binding partner, requiring the DACH1 ␣-helical DS domain which recruits corepressors to the local chromatin. Analysis of over 2,000 patients demonstrated increased nuclear DACH1 expression correlated inversely with cellular mitosis and predicted improved breast cancer patient survival. The cell fate determination factor, DACH1, arrests breast tumor proliferation and growth in vivo providing a new mechanistic and potential therapeutic insight into this common disease.
The molecular mechanisms underlying the development and progression of prostate cancer are poorly understood. AMP-activated protein kinase (AMPK) is a serine-threonine kinase that is activated in response to the hypoxic conditions found in human prostate cancers. In response to energy depletion, AMPK activation promotes metabolic changes to maintain cell proliferation and survival. Here, we report prevalent activation of AMPK in human prostate cancers and provide evidence that inhibition or depletion of AMPK leads to decreased cell proliferation and increased cell death. AMPK was highly activated in 40% of human prostate cancer specimens examined. Endogenous AMPK was active in both the androgensensitive LNCaP cells and the androgen-independent CWR22Rv1 human prostate cancer cells. Depletion of AMPK catalytic subunits by small interfering RNA or inhibition of AMPK activity with a small-molecule AMPK inhibitor (compound C) suppresses human prostate cancer cell proliferation. Apoptotic cell death was induced in LNCaP and CWR22Rv1 cells at compound C concentrations that inhibited AMPK activity. The evidence provided here is the first report that the activated AMPK pathway is involved in the growth and survival of human prostate cancer and offers novel potential targets for chemoprevention of human prostate cancer. [Mol Cancer Ther 2009;8(4):733-41]
Voltage-gated sodium (Nav) channels are required for impulse conductance in excitable tissues. Navs have been linked to human cancers, including prostate. The expression and distribution of Nav isoforms (Nav1.1-Nav1.9) in human prostate cancer are not well established. Here, we evaluated the expression of these isoforms and investigated the expression of Nav1.8 in human prostate cancer tissues. Nav1.8 was highly expressed in all examined cells. Expression of Nav1.1, Nav1.2, and Nav1.9 were high in DU-145, PC-3 and PC-3M cells compared to LNCaP (hormone-dependent), C4-2, C4-2B, and CWR22Rv-1 cells. Nav1.5 and Nav1.6 were expressed in all cells examined. Nav1.7 expression was absent in PC-3M and CWR22Rv-1, but expressed in the other cells examined. Immunohistochemistry revealed intensive Nav1.8 staining correlated with more advanced pathologic stage of disease. Increased intensity of nuclear Nav1.8 correlated with increased Gleason grade. Our results revealed that Nav1.8 is universally expressed in human prostate cancer cells. Nav1.8 expression statistically correlated with pathologic stage (P=0.04) and Gleason score (P=0.01) of human prostate tissue specimens. The aberrant nuclear localization of Nav1.8 with advanced prostate cancer tissues warrant further investigation into use of Nav1.8 as a potential biomarker to differentiate between early and advanced disease.
Two human immunoglobulin M (IgM) monoclonal antibodies (MoAbs), 16.88 and 28A32, which react with cytoplasmic (28A32 and 16.88) or cell surface (28A32) determinants on human colon carcinoma cells, were administered intravenously to 26 patients with metastatic colorectal carcinoma to determine if they could localize to sites of metastatic disease, if they had any antitumor or toxic effects, and to determine whether they would elicit an antihuman MoAb response. Serial scans showed tumor uptake of radioisotope in 12 of 16 patients receiving 131I-labeled 28A32 and in nine of 12 patients receiving 131I-labeled 16.88. No antitumor effects were seen with either antibody. No antibody-related toxic effects were observed following administration of 16.88, but two patients developed localized urticarial reactions following injection with antibody 28A32. No patient developed an antibody response to 16.88. Anti-28A32 reactivity was found in five of 12 (42%) normal sera and in seven of 23 (30%) patients before receiving any antibody. Following administration of 28A32, a low titer (1:10 dilution) of anti-28A32 developed in four patients with no preexisting antibody, a decrease in the preexisting titer was seen in three other patients, the titer remained constant in one patient, and no anti-28A32 was ever detected in six patients. In most cases, anti-28A32 activity was lost at dilutions greater than 1:10 and did not appear to affect antibody half-life in the serum or whole body retention of the antibody. We conclude that these human IgM MoAbs are capable of localizing at sites of disease in vivo, are nontoxic, and are poorly immunogenic in humans. Further studies to determine the specificity of targeting and to improve the delivery of antibody to sites of tumor are indicated.
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