SIK2 represses AKT/GSK3ß/ß-catenin signaling and suppresses gastric cancer by inhibiting autophagic degradation of protein phosphatases.

Salt-inducible kinase 2 (SIK2) is an important regulator in various intracellular signaling pathways related to apoptosis, tumorigenesis and metastasis. However, the involvement of SIK2 in gastric tumorigenesis and the functional linkage with gastric cancer (GC) progression remain to be defined. Here, we report that SIK2 was significantly downregulated in human GC tissues, and reduced SIK2 expression was associated with poor prognosis of patients. Overexpression of SIK2 suppressed the migration and invasion of GC cells, whereas knockdown of SIK2 enhanced cell migratory and invasive capability as well as metastatic potential. These changes in the malignant phenotype resulted from the ability of SIK2 to suppress epithelial-mesenchymal transition via inhibition of AKT/GSK3ß/ß-catenin signaling. The inhibitory effect of SIK2 on AKT/GSK3ß/ß-catenin signaling was mediated primarily through inactivation of AKT, due to its enhanced dephosphorylation by the upregulated protein phosphatases PHLPP2 and PP2A. The upregulation of PHLPP2 and PP2A was attributable to SIK2 phosphorylation and activation of mTORC1, which inhibited autophagic degradation of these two phosphatases. These results suggest that SIK2 acts as a tumor suppressor in GC and may serve as a novel prognostic biomarker and therapeutic target for this tumor.

Lymphocyte-to-monocyte ratio effectively predicts survival outcome of patients with obstructive colorectal cancer.

BACKGROUND: Obstructive colorectal cancer (OCC) is always accompanied by severe complications, and the optimal strategy for patients with OCC remains undetermined. Different from emergency surgery (ES), self-expandable metal stents (SEMS) as a bridge to surgery (BTS), could increase the likelihood of primary anastomosis. However, the stent failure and related complications might give rise to a high recurrence rate. Few studies have focused on the indications for either method, and the relationship between preoperative inflammation indexes and the prognosis of OCC is still underestimated. AIM: To explore the indications for ES and BTS in OCCs based on preoperative inflammation indexes. METHODS: One hundred and twenty-eight patients who underwent ES or BTS from 2008 to 2015 were enrolled. Receiver operating characteristic (ROC) curve analysis was used to define the optimal preoperative inflammation index and its cutoff point. Kaplan-Meier analyses and Cox proportional hazards models were applied to assess the association between the preoperative inflammation indexes and the survival outcomes [overall survival (OS) and disease-free survival (DFS)]. Stratification analysis was performed to identify the subgroups that would benefit from ES or BTS. RESULTS: OS and DFS were comparable between the ES and BTS groups (P > 0.05). ROC curve analysis showed derived neutrophil-to-lymphocyte ratio (dNLR) as the optimal biomarker for the prediction of DFS in ES (P < 0.05). Lymphocyte-to-monocyte ratio (LMR) was recommended for BTS with regard to OS and DFS (P < 0.05). dNLR was related to stoma construction (P = 0.001), pneumonia (P = 0.054), and DFS (P = 0.009) in ES. LMR was closely related to lymph node invasion (LVI) (P = 0.009), OS (P = 0.020), and DFS (P = 0.046) in the BTS group. dNLR was an independent risk factor for ES in both OS (P = 0.032) and DFS (P = 0.016). LMR affected OS (P = 0.053) and DFS (P = 0.052) in the BTS group. LMR could differentiate the OS between the ES and BTS groups (P < 0.05). CONCLUSION: Preoperative dNLR and LMR could predict OS and DFS in patients undergoing ES and BTS, respectively. For OCC, as the potential benefit group, patients with a low LMR might be preferred for BTS via SEMS insertion.

PI3K/AKT inhibitors aggravate death receptor-mediated hepatocyte apoptosis and liver injury.

The PI3K/AKT signaling pathway is one of the most frequently activated signaling networks in human cancers and has become a valuable target in anticancer therapy. However, accumulating reports suggest that adverse effects such as severe liver injury and inflammation may accompany treatment with pan-PI3K and pan-AKT inhibitors. Our prior work has demonstrated that activation of the PI3K/AKT pathway has a protective role in Fas- or TNFα-induced hepatocytic cell death and liver injury. We postulated that PI3K or AKT inhibitors may exacerbate liver damage via the death factor-mediated hepatocyte apoptosis. In this study we found that several drugs targeting PI3K/AKT either clinically used or in clinical trials sensitized hepatocytes to agonistic anti-Fas antibody- or TNFα-induced apoptosis and significantly shortened the survival of mice in in vivo liver damage models. The PI3K or AKT inhibitors promoted Fas aggregation, inhibited the expression of cellular FLICE-inhibitory protein S and L (FLIPL/S), and enhanced procaspase-8 activation. Conversely, cotreatment with the AKT specific activator SC79 reversed these effects. Taken together, these findings suggest that PI3K or AKT inhibitors may render hepatocytes hypersensitive to Fas- or TNFα-induced apoptosis and liver injury.

AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates d-Gal/LPS-induced liver injury.

Tumor necrosis factor-α (TNF-α) is a highly pleiotropic cytokine executing biological functions as diverse as cell proliferation, metabolic activation, inflammatory responses, and cell death. TNF-α can induce multiple mechanisms to initiate apoptosis in hepatocytes leading to the subsequent liver injury. Since the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway is known to have a protective role in death factor-mediated apoptosis, it is our hypothesis that activation of Akt may represent a therapeutic strategy to alleviate TNF-α-induced hepatocyte apoptosis and liver injury. We report here that the Akt activator SC79 protects hepatocytes from TNF-α-induced apoptosis and protects mice from d-galactosamine (d-Gal)/lipopolysaccharide (LPS)-induced TNF-α-mediated liver injury and damage. SC79 not only enhances the nuclear factor-κB (NF-κB) prosurvival signaling in response to TNF-α stimulation, but also increases the expression of cellular FLICE (FADD-like IL-1ß-converting enzyme)-inhibitory protein L and S (FLIPL/S), which consequently inhibits the activation of procaspase-8. Furthermore, pretreatment of the PI3K/Akt inhibitor LY294002 reverses all the SC79-induced hepatoprotective effects. These results strongly indicate that SC79 protects against TNF-α-induced hepatocyte apoptosis and suggests that SC79 is likely a promising therapeutic agent for ameliorating the development of liver injury. NEW & NOTEWORTHY SC79 protects hepatocytes from TNF-α-mediated apoptosis and mice from Gal/LPS-induced liver injury and damage. Cytoprotective effects of SC79 against TNF-α act through both AKT-mediated activation of NF-κB and upregulation of FLIPL/S.