Adhesion GPR123 is an indicator for recurrence and prognosis in bladder cancer.

BACKGROUND: Bladder cancer is a common urinary cancer, and most patients suffer tumor recurrence after surgery. Identifying more prognostic biomarkers is an essential task for precious treatment. OBJECTIVE: To evaluate the expression and clinical significance of GPR123, Angiotensin-I a type of adhesion G protein-coupled receptors (aGPCRs), in bladder cancer. METHODS: The expressions of GPR123 in two retrospective cohorts comprised of 150 and 56 patients with bladder cancer respectively, were detected with and immunohistochemistry (IHC). Moreover, GPR123 mRNAs in 11 non-muscle-invasive bladder cancers (NMIBCs) and 11 muscle-invasive bladder cancers (MIBCs) were detected with qRT-PCR. The correlation between GPR123 and the clinicopathological characters was estimated by Chi-square test. The significance of GPR123 and other clinicopathological characters in recurrence and prognosis of bladder cancer was evaluated by univariate and multivariate analyses. RESULTS: GPR123 was mainly expressed in the cell membrane of bladder cancer. The percentages of high GPR123 expression in NMIBC and MIBC were 38.32 and 55.81 % in cohort 1, and 16.00 and 43.90 % in cohort 2. With qRT-PCR and IHC, we showed that GPR123 expression in MIBC was significantly higher than that in NMIBC. GPR123 was significantly associated with T and M stage of bladder cancer. GPR123 expression was all correlated with recurrence (disease-free survival rate), and prognosis (overall survival rate). High GPR123 expression was identified as independent biomarker indicating easier recurrence and poorer prognosis. CONCLUSIONS: GPR123 was an independent biomarker of bladder cancer for recurrence and prognosis, indicating that GPR123 detection with IHC after operation could help find the high-risk patients and direct the post-operational surveillance.

Microsecond molecular dynamics simulations provide insight into the ATP-competitive inhibitor-induced allosteric protection of Akt kinase phosphorylation.

Akt is a serine/threonine protein kinase, a critical mediator of growth factor-induced survival in key cellular pathways. Allosteric signaling between protein intramolecular domains requires long-range communication mediated by hotspot residues, often triggered by ligand binding. Here, based on extensive 3 µs explicit solvent molecular dynamics (MD) simulations of Akt1 kinase domain in the unbound (apo) and ATP-competitive inhibitor, GDC-0068-bound states, we propose a molecular mechanism for allosteric regulation of Akt1 kinase phosphorylation by GDC-0068 binding to the ATP-binding site. MD simulations revealed that the apo Akt1 is flexible with two disengaged N- and C-lobes, equilibrated between the open and closed conformations. GDC-0068 occupancy of the ATP-binding site shifts the conformational equilibrium of Akt1 from the open conformation toward the closed conformation and stabilizes the closed state. This effect enables allosteric signal propagation from the GDC-0068 to the phosphorylated T308 (pT308) in the activation loop and restrains phosphatase access to pT308, thereby protecting the pT308 in the GDC-0068-bound Akt1. Importantly, functional hotspots involved in the allosteric communication from the GDC-0068 to the pT308 are identified. Our analysis of GDC-0068-induced allosteric protection of Akt kinase phosphorylation yields important new insights into the molecular mechanism of allosteric regulation of Akt kinase activity.