ABSTRACT
The detection of intracellular forms of Notch1 in human cervical cancers more than a decade ago prompted an investigation into the possible role of this pathway in driving these cancers. These tumors are consistently characterized by features of deregulated ligand-dependent signaling. Although Notch signaling complements the function of papillomavirus oncogenes in transformation assays of human keratinocytes, there are dose-dependent effects, which inhibit growth of established cervical cancer cell lines. Two pro-oncogenic effector mechanisms that have been suggested to operate in this context by Notch signaling are the activation of PI3K/Akt pathway and the upregulation of c-Myc. Collectively, there is a complex interplay between Notch signaling and papillomaviruses in the context of cervical carcinogenesis. Better animal model systems and identification of human cervical cancer stem cells should help clarify the possible stage specific and pleiotropic effects and regulation of Notch signaling.
Subject(s)
Neoplasm Proteins/physiology , Receptor, Notch1/physiology , Uterine Cervical Neoplasms/physiopathology , Adenoviridae Infections/physiopathology , Animals , Apoptosis , Cell Transformation, Neoplastic , Cell Transformation, Viral , Disease Progression , Female , Humans , Keratinocytes/virology , Mice , NF-kappa B/physiology , Neoplasms/physiopathology , Oncogene Proteins, Viral/physiology , Papillomavirus Infections/physiopathology , Phosphatidylinositol 3-Kinases/physiology , Proto-Oncogene Proteins c-akt/physiology , Proto-Oncogene Proteins c-myc/physiology , Uterine Cervical Neoplasms/virologyABSTRACT
Curcumin (diferuloyl methane), the yellow pigment in turmeric (Curcuma longa), is a potent chemopreventive agent. Curcumin induces apoptosis of several, but not all, cancer cells. Many cancer cells protect themselves against apoptosis by activating nuclear factor-kappaB (NF-kappaB)/Rel, a transcription factor that helps in cell survival. Signal-induced activation of NF-kappaB is known to be inhibited by curcumin. To understand the role of NF-kappaB in curcumin-induced apoptosis, we stably transfected relA gene encoding the p65/RelA subunit of NF-kappaB, into l-929 cells (mouse fibrosarcoma) and the relA-transfected cells were resistant to varying doses of curcumin (10(-6)-10(-4) m), whereas the parental cells underwent apoptosis in a time- and dose-dependent manner. The relA-transfected cells showed constitutive NF-kappaB DNA binding activity that could not be inhibited by curcumin and did not show nuclear condensation and DNA fragmentation upon treatment with curcumin. When a super-repressor form of IkappaB-alpha (known to inhibit NF-kappaB) was transfected transiently into relA-transfected cells, the cells were no longer resistant to curcumin. Our results highlight a critical anti-apoptotic role for NF-kappaB in curcumin-induced apoptosis.
Subject(s)
Apoptosis/drug effects , Curcumin/pharmacology , I-kappa B Proteins , NF-kappa B/genetics , Animals , DNA Fragmentation/drug effects , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , NF-KappaB Inhibitor alpha , NF-kappa B/metabolism , Transcription Factor RelA , Transfection , Tumor Cells, CulturedABSTRACT
The role of thyroid hormones in DNA synthesis and in the activity of Thymidine kinase (TK), a key regulatory enzyme of DNA synthesis was studied in proliferating hepatocytes in vivo. Liver regeneration after partial hepatectomy was used as a model for controlled cell division in rats having different thyroid status - euthyroid, hypothyroid and 3,3',5'-triiodo-L-thyronine (T3)-treated hypothyroid. Partial hepatectomy caused a significant elevation of DNA synthesis (p<0.01) in all the three groups compared to their sham-operated counterparts. Hypothyroid hepatectomised animals showed significantly lower (p<0.01) level of DNA synthesis than euthyroid hepatectomised animals. A single subcutaneous dose of T3 to hypothyroid sham-operated animals resulted in a significant increase (p<0.01) of DNA synthesis in the intact liver. This was comparable to the level of DNA synthesis occurring in regenerating liver of euthyroid animals. In hypothyroid hepatectomised animals, T3 showed an additive effect on DNA synthesis and this group exhibited maximum level of DNA synthesis (p<0.01). Studies of the kinetic parameters of TK show that the Michelis-Menten constant, (K(m)) of TK for thymidine was altered by the thyroid status. K(m) increased significantly (p<0.01) in untreated hypothyroid animals when compared to the euthyroid rats. T3 treatment of hypothyroid animals reversed this effect and this group showed the lowest value for K(m) (p<0.01). Thus our results indicate that thyroid hormones can influence DNA synthesis during liver regeneration and they may regulate the activity of enzymes such as Thymidine kinase which are important for DNA synthesis and hence cell division.
