We genotyped 70 genes involved in the pathogenesis of renal-cell carcinoma (including the VHL/HIF/VEGF and PI3K/AKT/mTOR pathways, and genes involved in immune regulation and metabolism) for single nucleotide polymorphisms.
Interruption of PI3K→︀AKT→︀GSK3β→︀AM signaling via specific inhibitors led to decreased recruitment of mast cells, and targeting this infiltrating mast cell-related signaling via an AKT-specific inhibitor suppressed RCC angiogenesis in xenograft mouse models.
Among 184 everolimus-treated patients with RCC with NGS data, mutation rates in genes of interest were 6% (<i>TSC1</i>), 4.4% (<i>TSC2</i>), and 8.2% (<i>mTOR</i>); 44% harbored alterations in ≥1 PI3K pathway component.
Gain of function experiments showed overexpression of PTEN-Long in the ccRCC cell line 786-0 suppressed PI3K-Akt signaling, inhibited cell proliferation, migration and invasion, and eventually induced cell death.
Together, our study reveals a novel mechanism of PI3K-AKT inhibition-mediated feedback regulation and may identify FoxO as a novel biomarker to stratify patients with RCC for PI3K or AKT inhibitor treatment, or a novel therapeutic target to synergize with PI3K-AKT inhibition in RCC treatment.
The PI3K/Akt pathway and other pathways associated with cyclins, DNA replication and cell cycle/mitotic regulation were also associated with the synergy of DAC and PTX against RCC.
The results showed that downregulation of the tumor suppressor gene PTEN expression and the inhibition of PTEN/PI3K/AKT cell signaling pathway may be involved in the occurrence and development of RCC in children.
Other newly identified pathways and components recurrently mutated in ccRCC included PI3K-AKT-mTOR signaling, the KEAP1-NRF2-CUL3 apparatus, DNA methylation, p53-related pathways and mRNA processing.
Overall, miR‑205‑5p functions as a tumor suppressor in RCC by targeting VEGFA and the PI3K/Akt signaling pathway, providing a potential therapeutic target for the treatment of ccRCC.
The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells.
The optimal silencing si-RNA was subsequently selected and RCC cell lines 786-O and A498 were selected and transfected with either a si-PDK1 or activator of the PI3K-PDK1-Akt pathway for grouping purposes.
Numerous signaling pathways, such as PI3K/Akt/mTOR and Wnt‑β‑catenin have been demonstrated to be associated with the tumorigenesis and development of RCC.
Renal cell carcinoma (RCC) is a metabolic disease, being characterized by the dysregulation of metabolic pathways involved in oxygen sensing (VHL/HIF pathway alterations and the subsequent up-regulation of HIF-responsive genes such as VEGF, PDGF, EGF, and glucose transporters GLUT1 and GLUT4, which justify the RCC reliance on aerobic glycolysis), energy sensing (fumarate hydratase-deficient, succinate dehydrogenase-deficient RCC, mutations of HGF/MET pathway resulting in the metabolic Warburg shift marked by RCC increased dependence on aerobic glycolysis and the pentose phosphate shunt, augmented lipogenesis, and reduced AMPK and Krebs cycle activity) and/or nutrient sensing cascade (deregulation of AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways).
In this article, we briefly review current evidence regarding mechanisms of resistance in RCC and treatment strategies to overcome resistance with a special focus on the PI3K/AKT/mTOR pathway.
Using specific inhibitors of phosphoinositide 3-kinase (PI3K) and depletion of Akt kinase by RNA interference, we established that PTHrP is one of the main factor involved in the constitutive activation of this pathway in human RCC, independently of von Hippel-Lindau (VHL) tumor suppressor gene expression.
In this study, we demonstrated that the levels of RAGE/HMGB1 and autophagic protein LC3, Beclin-1, PI3K were much higher in ccRCC samples than those of in adjacent normal tissues.