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1.
Photochem Photobiol Sci ; 23(6): 1067-1075, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38625651

ABSTRACT

Photodynamic Therapy (PDT) is an emerging method to treat colorectal cancers (CRC). Hypericin (HYP) is an effective mediator of PDT and the ABCG2 inhibitor, Febuxostat (FBX) could augment PDT. HT29 and HEK293 cells showed light dependant cytotoxic response to PDT in both 2D and 3D cell models. FBX co-treatment was not found to improve PDT cytotoxicity. Next, ABCG2 protein expression was observed in HT29 but not in HEK293 cells. However, ABCG2 gene expression analysis did not support protein expression results as ABCG2 gene expression results were found to be higher in HEK293 cells. Although HYP treatment was found to significantly reduce ABCG2 gene expression levels in both cell lines, FBX treatment partially restored ABCG2 gene expression. Our findings indicate that FBX co-treatment may not be suitable for augmenting HYP-mediated PDT in CRC but could potentially be useful for other applications.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2 , Anthracenes , Colorectal Neoplasms , Febuxostat , Neoplasm Proteins , Perylene , Photochemotherapy , Photosensitizing Agents , Humans , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Anthracenes/pharmacology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Perylene/analogs & derivatives , Perylene/pharmacology , Febuxostat/pharmacology , Febuxostat/therapeutic use , Neoplasm Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , HEK293 Cells , Cell Survival/drug effects , HT29 Cells , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry
2.
Am J Hum Genet ; 111(1): 119-132, 2024 Jan 04.
Article in English | MEDLINE | ID: mdl-38141607

ABSTRACT

Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.


Subject(s)
Megalencephaly , Proto-Oncogene Proteins c-myc , Humans , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Dimerization , Megalencephaly/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism
3.
Genes (Basel) ; 14(7)2023 07 14.
Article in English | MEDLINE | ID: mdl-37510349

ABSTRACT

D-type cyclins encode G1/S cell cycle checkpoint proteins, which play a crucial role in defining cell cycle exit and progression. Precise control of cell cycle exit is vital during embryonic development, with defects in the pathways regulating intracellular D-type cyclins resulting in abnormal initiation of stem cell differentiation in a variety of different organ systems. Furthermore, stabilisation of D-type cyclins is observed in a wide range of disorders characterized by cellular over-proliferation, including cancers and overgrowth disorders. In this review, we will summarize and compare the roles played by each D-type cyclin during development and provide examples of how their intracellular dysregulation can be an underlying cause of disease.


Subject(s)
Cyclins , Cyclins/genetics , Cyclins/metabolism , Cyclin D3 , Cell Division , Cell Cycle/genetics , Cell Proliferation
4.
J Exp Med ; 202(7): 975-86, 2005 Oct 03.
Article in English | MEDLINE | ID: mdl-16203867

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel localized primarily at the apical or luminal surfaces of epithelial cells that line the airway, gut, and exocrine glands; it is well established that CFTR plays a pivotal role in cholera toxin (CTX)-induced secretory diarrhea. Lysophosphatidic acid (LPA), a naturally occurring phospholipid present in blood and foods, has been reported to play a vital role in a variety of conditions involving gastrointestinal wound repair, apoptosis, inflammatory bowel disease, and diarrhea. Here we show, for the first time, that type 2 LPA receptors (LPA2) are expressed at the apical surface of intestinal epithelial cells, where they form a macromolecular complex with Na+/H+ exchanger regulatory factor-2 and CFTR through a PSD95/Dlg/ZO-1-based interaction. LPA inhibited CFTR-dependent iodide efflux through LPA2-mediated Gi pathway, and LPA inhibited CFTR-mediated short-circuit currents in a compartmentalized fashion. CFTR-dependent intestinal fluid secretion induced by CTX in mice was reduced substantially by LPA administration; disruption of this complex using a cell-permeant LPA2-specific peptide reversed LPA2-mediated inhibition. Thus, LPA-rich foods may represent an alternative method of treating certain forms of diarrhea.


Subject(s)
Cholera Toxin/antagonists & inhibitors , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Diarrhea/drug therapy , Lysophospholipids/pharmacology , Analysis of Variance , Animals , Cell Line , Cell Line, Tumor , Chlorocebus aethiops , Cholera Toxin/toxicity , Cricetinae , Cyclic AMP/metabolism , Cytoskeletal Proteins/metabolism , Diarrhea/chemically induced , Disks Large Homolog 4 Protein , Epithelial Cells/metabolism , Humans , Immunoblotting , Immunoprecipitation , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Phosphoproteins/metabolism , Sodium-Hydrogen Exchangers , Zonula Occludens-1 Protein
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