cAMP-dependent pathway is one of the most significant signaling cascades in healthy and neoplastic ovarian cells. Working through its major effector proteins—PKA and EPAC—it regulates gene expression and many cellular functions. PKA promotes the phosphorylation of cAMP response element-binding protein (CREB) which mediates gene transcription, cell migration, mitochondrial homeostasis, cell proliferation, and death. EPAC, on the other hand, is involved in cell adhesion, binding, differentiation, and interaction between cell junctions. Ovarian cancer growth and metabolism largely depend on changes in the signal processing of the cAMP-PKA-CREB axis, often associated with neoplastic transformation, metastasis, proliferation, and inhibition of apoptosis. In addition, the intracellular level of cAMP also determines the course of other pathways including AKT, ERK, MAPK, and mTOR, that are hypo- or hyperactivated among patients with ovarian neoplasm. With this review, we summarize the current findings on cAMP signaling in the ovary and its association with carcinogenesis, multiplication, metastasis, and survival of cancer cells. Additionally, we indicate that targeting particular stages of cAMP-dependent processes might provide promising therapeutic opportunities for the effective management of patients with ovarian cancer.

Epithelial ovarian cancer has the highest mortality among all gynecological malignancies. The main reasons for high mortality are late diagnosis and development of resistance to chemotherapy. Resistance to chemotherapeutic drugs can result from altered expression of drug-resistance genes regulated by miRNA. The main goal of our study was to detect differences in miRNA expression levels in two doxorubicin (DOX)- and two topotecan (TOP)-resistant variants of the A2780 drug-sensitive ovarian cancer cell line by miRNA microarray. The next aim was to recognize miRNAs as factors responsible for the regulation of drug-resistance genes. We observed altered expression of 28 miRNA that may be related to drug resistance. The upregulation of miR-125b-5p and miR-935 and downregulation of miR-218-5p was observed in both DOX-resistant cell lines. In both TOP-resistant cell lines, we noted the overexpression of miR-99a-5p, miR-100-5p, miR-125b-5p, and miR-125b-2-3p and decreased expression of miR-551b-3p, miR-551b-5p, and miR-383-5p. Analysis of the targets suggested that expression of important drug-resistant genes such as the collagen type I alpha 2 chain (COL1A2), protein Tyrosine Phosphatase Receptor Type K (PTPRK), receptor tyrosine kinase—EPHA7, Roundabout Guidance Receptor 2 (ROBO2), myristoylated alanine-rich C-kinase substrate (MARCK), and the ATP-binding cassette subfamily G member 2 (ABCG2) can be regulated by miRNA.

Previously, we reported a new missense mutation in the ANK1 gene that correlated with the hereditary spherocytosis phenotype. This mutation, resulting in L1340P substitution (HGMD CM149731), likely leads to the changes in the conformation of the ankyrin ZZUD domain important for ankyrin binding to spectrin. Here, we report the molecular and physiological effects of this mutation. First, we assessed the binding activity of human β-spectrin to the mutated ZZUDL1340P domain of ankyrin using two different experimental approaches—the study of association and dissociation responses of the spectrin–ankyrin binding domain and a sedimentation assay. In addition, we documented the changes in morphology caused by the overexpressed ankyrin ZZUD domain in human cell models. Our results prove the key role of the L1340 aa residue for the correct alignment of the ZZUD domain of ankyrin, which results in binding the latter with spectrin within the erythrocyte membrane. Replacing L1340 with a proline residue disrupts the spectrin-binding activity of ankyrin.

Previously, we reported a new missense mutation in the ANK1 gene correlated with the HS phenotype. This mutation, resulting in L1340P substitution (HGMD CM149731), likely leads to the changes in the conformation of the ankyrin ZZUD domain important for ankyrin binding to spectrin. In this report, we have shown the molecular and physiological effects of this mutation. First, we assessed the binding activity of human beta-spectrin to the mutated ZZUDL1340P domain of ankyrin using two different experimental approaches: the study of association and dissociation responses of spectrin ankyrin binding domain and sedimentation assay. In addition, we demonstrated changes in morphology caused by the overexpressed ankyrin ZZUD domain in human cell models. Our results prove the key role of L1340 aa residue in the UPA domain for the correct alignment of the ZZUD domain of ankyrin, which results in binding the latter with spectrin within the erythrocyte membrane. Replacing the L1340 with a proline residue disrupts the spectrin binding activity of ankyrin.

Autosomal recessive polycystic kidney disease (ARPKD) is caused primarily by mutations in PKHD1, encoding fibrocystin (FPC), but Pkhd1 mutant mice failed to reproduce the human phenotype. In contrast, the renal lesion in congenital polycystic kidney (cpk) mice, with a mutation in Cys1 and cystin protein loss, closely phenocopies ARPKD. Although the nonhomologous mutation diminished the translational relevance of the cpk model, recent identification of patients with CYS1 mutations and ARPKD prompted the investigations described herein. We examined cystin and FPC expression in mouse models (cpk, rescuedcpk (r-cpk), Pkhd1 mutants) and mouse cortical collecting duct (CCD) cell lines (wild type (wt), cpk). We found that cystin deficiency caused FPC loss in both cpk kidneys and CCD cells. FPC levels increased in r-cpk kidneys and siRNA of Cys1 in wt cells reduced FPC. However, FPC deficiency in Pkhd1 mutants did