Project description:Protein kinase C (PKC) is a large family of calcium- and phospholipid-dependent serine/threonine kinases that consists of at least 11 isozymes. Based on their structural characteristics and mode of activation, the PKC family is classified into three subfamilies: conventional or classic (cPKCs; α, βI, βII, and γ), novel or non-classic (nPKCs; δ, ε, η, and θ), and atypical (aPKCs; ζ, ι, and λ) (PKCλ is the mouse homolog of PKCι) PKC isozymes. PKC isozymes play important roles in proliferation, differentiation, survival, migration, invasion, apoptosis, and anticancer drug resistance in cancer cells. Several studies have shown a positive relationship between PKC isozymes and poor disease-free survival, poor survival following anticancer drug treatment, and increased recurrence. Furthermore, a higher level of PKC activation has been reported in cancer tissues compared to that in normal tissues. These data suggest that PKC isozymes represent potential diagnostic and prognostic biomarkers and therapeutic targets for cancer. This review summarizes the current knowledge and discusses the potential of PKC isozymes as biomarkers in the diagnosis, prognosis, and treatment of cancers.
Project description:Although the concept of cancer stem cells (CSCs) is well-accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In this study, we demonstrate the existence of human melanoma cells that fulfill the criteria for CSCs (self-renewal and differentiation) by serially xenotransplanting cells into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH-positive melanoma cells are more tumorigenic than ALDH-negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH-positive melanoma cells reveal the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA or shRNA leads to cell cycle arrest, apoptosis, decreased cell viability in vitro, and reduced tumorigenesis in vivo. ALDH-positive melanoma cells are more resistant to chemotherapeutic agents and silencing ALDH1A by siRNA sensitizes melanoma cells to drug-induced cell death. Furthermore, we, for the first time, examined the molecular signatures of ALDH-positive CSCs from patient-derived tumor specimens. The signatures of melanoma CSCs include retinoic acid (RA)-driven target genes with RA response elements and genes associated with stem cell function. These findings implicate that ALDH isozymes are not only biomarkers of CSCs but also attractive therapeutic targets for human melanoma. Further investigation of these isozymes and genes will enhance our understanding of the molecular mechanisms governing CSCs and reveal new molecular targets for therapeutic intervention of cancer.
Project description:MicroRNAs (miRNAs) are evolutionarily conserved, small, regulatory RNAs that negatively regulate gene expression. Extensive research in the last decade has implicated miRNAs as master regulators of cellular processes with essential role in cancer initiation, progression, and metastasis, making them promising therapeutic tools for cancer management. In this article, we will briefly review the structure, biogenesis, functions, and mechanism of action of these miRNAs, followed by a detailed analysis of the therapeutic potential of these miRNAs. We will focus on the strategies presently used for miRNA therapy; discuss their use and drawbacks; and the challenges and future directions for the development of miRNA-based therapy for human cancers.
Project description:The main role of condensins is to regulate chromosome condensation and segregation during cell cycles. Recently, it has been suggested in the literatures that subunits of condensin I and condensin II are involved in some human cancers. This paper will first briefly discuss discoveries of human condensins, their components and structures, and their multiple cellular functions. This will be followed by reviews of most recent studies on subunits of human condensins and their dysregulations or mutations in human cancers. It can be concluded that many of these subunits have potentials to be novel targets for cancer therapies. However, hCAP-D2, a subunit of human condensin I, has not been directly documented to be associated with any human cancers to date. This review hypothesizes that hCAP-D2 can also be a potential therapeutic target for human cancers, and therefore that all subunits of human condensins are potential therapeutic targets for human cancers.
Project description:The intrinsic activity of the C-terminal catalytic (C) domain of cyclic guanosine monophosphate (cGMP)-dependent protein kinases (PKG) is inhibited by interactions with the N-terminal regulatory (R) domain. Selective binding of cGMP to cyclic nucleotide binding (CNB) domains within the R-domain disrupts the inhibitory R-C interaction, leading to the release and activation of the C-domain. Affinity measurements of mammalian and plasmodium PKG CNB domains reveal different degrees of cyclic nucleotide affinity and selectivity; the CNB domains adjacent to the C-domain are more cGMP selective and therefore critical for cGMP-dependent activation. Crystal structures of isolated CNB domains in the presence and absence of cyclic nucleotides reveal isozyme-specific contacts that explain cyclic nucleotide selectivity and conformational changes that accompany CNB. Crystal structures of tandem CNB domains identify two types of CNB-mediated dimeric contacts that indicate cGMP-driven reorganization of domain-domain interfaces that include large conformational changes. Here, we review the available structural and functional information of PKG CNB domains that further advance our understanding of cGMP mediated regulation and activation of PKG isozymes.
Project description:Connexins (Cx) are members of a protein family that forms intercellular channels localised in gap junction (GJ) plaques and single transmembrane channels called hemichannels. They participate in intercellular communication or communication between the intracellular and extracellular environments. Connexins affect cell homeostasis, growth and differentiation by enabling the exchange of metabolites or by interfering with various signalling pathways. Alterations in the functionality and the expression of connexins have been linked to the occurrence of many diseases. Connexins have been already linked to cancers, cardiac and brain disorders, chronic lung and kidney conditions and wound healing processes. Connexins have been shown either to suppress cancer tumour growth or to increase tumorigenicity by promoting cancer cell growth, migration and invasiveness. A better understanding of the complexity of cancer biology related to connexins and intercellular communication could result in the design of novel therapeutic strategies. The modulation of connexin expression may be an effective therapeutic approach in some types of cancers. Therefore, one important challenge is the search for mechanisms and new drugs, selectively modulating the expression of various connexin isoforms. We performed a systematic literature search up to February 2020 in the electronic databases PubMed and EMBASE. Our search terms were as follows: connexins, hemichannels, cancer and cancer treatment. This review aims to provide information about the role of connexins and gap junctions in cancer, as well as to discuss possible therapeutic options that are currently being studied.
Project description:Integrins are transmembrane receptors that are central to the biology of many human pathologies. Classically mediating cell-extracellular matrix and cell-cell interaction, and with an emerging role as local activators of TGFβ, they influence cancer, fibrosis, thrombosis and inflammation. Their ligand binding and some regulatory sites are extracellular and sensitive to pharmacological intervention, as proven by the clinical success of seven drugs targeting them. The six drugs on the market in 2016 generated revenues of some US$3.5 billion, mainly from inhibitors of α4-series integrins. In this review we examine the current developments in integrin therapeutics, especially in cancer, and comment on the health economic implications of these developments.
Project description:During neonatal hippocampal development, serotonin 1A receptor-mediated signaling initially employs PKCepsilon to boost neuronal proliferation and then uses PKCalpha to promote synaptogenesis. Such stage-specific involvement of a PKC isozyme could be determined by its relative expression level. In mouse hippocampi, we detected relatively low levels of alpha, beta, gamma, and delta isozymes at postnatal days 2-6 (P2-6), which was followed by a large increase in their expression. In contrast, the PKC isozymes epsilon and theta were relatively abundant at P6, following which they underwent a further increase by P15. Comparison with purified proteins confirmed that the PKCepsilon levels at P6 and P15 were respectively 1.75 and 7.36 ng per 60 microg of protein, whereas PKCalpha levels at P6 and P15 were respectively 160 pg and 1.186 ng per 60 microg of protein. Therefore, at P6, PKCepsilon was about 11-fold more abundant than PKCalpha. Consequently, signaling cascades could use the relatively abundant PKCepsilon (and possibly PKCtheta) molecules for early events at P2-6 (e.g. neurogenesis), following which PKCalpha (and the beta, gamma, or delta isozymes) could guide maturation or apoptosis. Notably, at P6 but not P15, PKCepsilon, was localized to the nuclei of neuroblasts, probably directing mitosis. In contrast, at P15 but not P6, PKCalpha was highly expressed in the processes of the differentiated hippocampal neurons. In summary, PKC isozymes follow differential profiles of expression in neonatal hippocampus and the relative abundance of each may determine its mode and stage of involvement in hippocampal development.
Project description:Bladder cancer has been linked to numerous toxins which can be concentrated in the bladder after being absorbed into the blood and filtered by the kidneys. Excessive carcinogenic load to the bladder urothelium may result in the development of cancer. However, enzymes within the bladder can metabolize carcinogens into substrates that are safer. Importantly, these proteins, namely the UGT's (uridine 5'-diphospho-glucuronosyltransferases), have been shown to possibly prevent bladder cancer. Also, studies have shown that the UGT1 expression is decreased in uroepithelial carcinomas, which may allow for the accumulation of carcinogens in the bladder. In this review, we discuss the UGT system and its' protective role against bladder cancer, UGT genetic mutations that modulate risk from chemicals and environmental toxins, as well as targeting of the UGT enzymes by nuclear receptors.
Project description:Radiation-inducible neo-antigens are proteins expressed on cancer cell surface after exposure to ionizing radiation (IR). These neo-antigens provide opportunities to specifically target cancers while sparing normal tissues. Tax interacting protein-1 (TIP-1) is induced by irradiation and is translocated to the surface of cancer cells. We have developed a monoclonal antibody, 2C6F3, against TIP-1.Epitope mapping revealed that 2C6F3 binds to the QPVTAVVQRV epitope of the TIP-1 protein. 2C6F3 binds to the surface of lung cancer (A549, LLC) and glioma (D54, GL261) cell lines. 2C6F3 binds specifically to TIP-1 and ELISA analysis showed that unconjugated 2C6F3 efficiently blocked binding of radiolabeled 2C6F3 to purified TIP-1 protein. To study in vivo tumor binding, we injected near infrared (NIR) fluorochrome-conjugated 2C6F3 via tail vein in mice bearing subcutaneous LLC and GL261 heterotopic tumors. The NIR images indicated that 2C6F3 bound specifically to irradiated LLC and GL261 tumors, with little or no binding in un-irradiated tumors.We also determined the specificity of 2C6F3 to bind tumors in vivo using SPECT/CT imaging. 2C6F3 was conjugated with diethylene triamine penta acetic acid (DTPA) chelator and radiolabeled with 111Indium (111In). SPECT/CT imaging revealed that 111In-2C6F3 bound more to the irradiated LLC tumors compared to un-irradiated tumors. Furthermore, injection of DTPA-2C6F3 labeled with the therapeutic radioisotope, 90Y, (90Y-DTPA-2C6F3) significantly delayed LLC tumor growth. 2C6F3 mediated antibody dependent cell-mediated cytotoxicity (ADCC) and antibody dependent cell-mediated phagocytosis (ADCP) in vitro.In conclusion, the monoclonal antibody 2C6F3 binds specifically to TIP-1 on cancer and radio-immunoconjugated 2C6F3 improves tumor control.