Complex roles of cAMP–PKA–CREB signaling in cancer

Cyclic adenosine monophosphate (cAMP) is the first discovered second messenger, which plays pivotal roles in cell signaling, and regulates many physiological and pathological processes. cAMP can regulate the transcription of various target genes, mainly through protein kinase A (PKA) and its downstream effectors such as cAMP-responsive element binding protein (CREB). In addition, PKA can phosphorylate many kinases such as Raf, GSK3 and FAK. Aberrant cAMP–PKA signaling is involved in various types of human tumors. Especially, cAMP signaling may have both tumor-suppressive and tumor-promoting roles depending on the tumor types and context. cAMP–PKA signaling can regulate cancer cell growth, migration, invasion and metabolism. This review highlights the important roles of cAMP–PKA–CREB signaling in tumorigenesis. The potential strategies to target this pathway for cancer therapy are also discussed.

Corosolic Acid Inhibits Cancer Progress Through Inactivating YAP in Hepatocellular Carcinoma

Chemotherapy is critical for the treatment of hepatocellular carcinoma (HCC). Despite the proapoptotic effects of corosolic acid (CA) treatment, its underlying mechanism is not completely clear. The aim of this study was to determine the molecular mechanism of CA in HCC treatment. MTT assay was used to determine the IC50 of CA. Immunoprecipitation and immunofluorescence were used to detect the interaction and subcellular localization of Yes-associated protein (YAP) and mouse double minute 2 (MDM2). In addition, in vivo xenotransplantation was performed to assess the effects of CA, YAP, and MDM2 on tumorigenesis. The IC50 of CA was about 40 M in different HCC cell lines, and CA decreased YAP expression by reducing its stability and increasing its ubiquitination. CA treatment and MDM2 overexpression significantly decreased the crosstalk between YAP and cAMP-responsive element-binding protein (CREB), TEA domain transcription factor (TEAD), and Runt-related transcription factor 2 (Runx2). CA stimulation promoted the translocation of YAP and MDM2 from the nucleus to the cytoplasm and increased their binding. In addition, CA treatment obviously reduced tumorigenesis, whereas this effect was abolished when cells were transfected with sh-MDM2 or Vector-YAP. The present study uncovered that CA induced cancer progress repression through translocating YAP from the nucleus in HCC, which might provide a new therapeutic target for HCC.

The Relationship Between cAMP Responsive Element Binding Protein and Its Phosphorylated Form in Cardiac Myxoma with DNA Mutation of Protein Kinase cAMP-Dependent Type I Regulatory Subunit Alpha

Considering the lack of information regarding the role and mechanism of low expression of PRKAR1α in cardiac myxoma, we investigated the relationship between the low expression of PRKAR1α and the cAMP responsive element binding protein (CREB) and the expression of its phosphorylated form (p-CREB) in cardiac myxoma tissue. For this purpose, we conducted a retrospective analysis of 130 cases of CM tissue obtained by surgical resection, from which paraffin-fixed tissue DNA was extracted, followed by detection of PRKAR1A DNA mutation by Sanger sequencing and detection of CREB, p-CREB, and PKAR1α protein expression by immunohistochemical SP method. Mutations in the PRKAR1A gene coding region were detected in 35 (46.05%) of 76 sporadic CM tissues, of which 48.57% (17/35 cases) had more than two mutations, and 28.57% (10/35 cases) had exon4: C.349-4-C.349-5insertTmutation. Compared with the surrounding normal tissues, 55.26% (42/76 cases) of PKAR1α protein was not expressed or weakly expressed, CREB was not expressed in myxoma and myocardial tissues, p-CREB was expressed in 51 (67.11%) CM-positive tissues, and PKAR1α and p-CREB expression demonstrated no correlation (P > 0.05). These results indicate the presence of a high level of CREB phosphorylation in cardiac myxoma tissue; however, its phosphorylation is not associated with mutations in the PRKAR1A gene coding region and PKAR1α expression.

Intrauterine low-protein diet aggravates developmental abnormalities of the urinary system via the Akt/Creb3 pathway in Robo2 mutant mice

The offspring of Robo2 mutant mice usually present with variable phenotypes of congenital anomalies of the kidney and urinary tract (CAKUT). An intrauterine low-protein diet can also cause CAKUT in offspring, dominated by the duplicated collecting system phenotype. A single genetic or environment factor can only partially explain the pathogenesis of CAKUT. The present study aimed to establish an intrauterine low-protein diet roundabout 2 ( Robo2) mutant mouse model and found that the intrauterine low-protein diet led to significantly increased CAKUT phenotypes in Robo2PB/+ mice offspring, dominant by a duplicated collecting system. At the same time, more ectopic and lower located ureteric buds (UBs) were observed in the intrauterine low-protein diet-fed Robo2 mutant mouse model, and the number of UB branches was reduced in the serum-free culture. During UB protrusion, intrauterine low-protein diet reduced the expression of Slit2/Robo2 in Robo2 mutant mice and affected the expression of glial cell-derived neurotrophic factor/Ret, which is a key molecule for metanephric development, with increasing phospho-Akt and phospho-cAMP responsive element-binding protein 3 activity and a reduction of apoptotic cells in embryonic day 11.5 UB tissues. The mechanism by which an intrauterine low-protein diet aggravates CAKUT in Robo2 mutant mice may be related to the disruption of Akt/cAMP responsive element-binding protein 3 signaling and a reduction in apoptosis in UB tissue.