Phosphatidylinositol‐3′‐kinase/AKT signaling is essential in synovial sarcoma

Abstract

Synovial sarcomas account for 5-10% of all malignant soft tissue tumors. They have been shown to express different membranous growth factor receptors, many of them signaling via intracellular kinase cascades. In our study, the functional role of PI3K/AKT signals in synovial sarcoma is analyzed with regard to tumor biology and therapeutic applicability. Immunohistochemical stainings of (Ser473)-phosphorylated (p)-AKT, its targets p-(Ser9)-GSK-3b and p-(Ser2448)-mTOR and the cell cycle regulators Cyclin D1 and p27 KIP1 were performed in 36 synovial sarcomas. The PIK3CA gene was screened for mutations. In vitro, four synovial sarcoma cell lines were treated with the PI3K inhibitor LY294002. Phosphorylation of AKT, GSK-3b and mTOR was assessed, and cellular proliferation and apoptosis were analyzed to functionally characterize the effects of PI3K inhibition. Finally, coincubations of LY294002 with cytotoxic drugs were performed. Most tumors showed significant expression levels of p-AKT, p-GSK-3b and p-mTOR, indicating activation of the PI3K/AKT signaling cascade in synovial sarcomas; Cyclin D1 and p27 KIP1 were differentially expressed. Mutations in the PIK3CA gene could be excluded. In vitro, PI3K inhibition diminished synovial sarcoma cell growth accompanied by reduced phosphorylation of AKT, GSK-3b and mTOR. Mechanistically, PI3K pathway inhibition lead to enhanced apoptosis and decreased cellular proliferation linked to reduced Cyclin D1 and increased p27 KIP1 levels. Simultaneous treatment of synovial sarcoma cell lines with LY294002 and cytotoxic drugs resulted in additive effects. In summary, PI3K signaling plays an essential role in growth control of synovial sarcomas and might be successfully targeted in multimodal therapeutic strategies.

Prognostic impact of the activation status of the Akt/mTOR pathway in synovial sarcoma

“…This epithelioiddominant staining pattern was mentioned in a previous study. 5 However, its significance remains unclear, because this pattern had no correlation with other clinicopathologic parameters in the current study. Patients who had pAkt-positive tumors had a better clinical response to chemotherapy than those who had tumors that were negative for pAkt, and this tendency was not observed for the other molecular markers.…”

“…Several previous studies have demonstrated the activation of this pathway and its contribution to cell survival and proliferation in SS in vitro. 3,5 However, the expression profiles of the molecules along the Akt/mTOR pathway have been analyzed in a relatively small number of clinical materials. 5,13,14 Some authors investigated Akt/mTOR pathway involvement in STS series and demonstrated a correlation between Akt activation and a worse prognosis 15 or a greater probability of metastasis 13 ; whereas, to our knowledge, no investigations have focused on SS as a single entity, and the prognostic impact of this pathway on SS has remained to be clarified.…”

“…These results are consistent with the recent findings of some investigators who reported only rare PIK3CA mutation in SS. 5,23,24 Previous studies have indicated another potential factor in the Akt/mTOR pathway: the activation of receptor tyrosine kinases or cytokine receptors. Epidermal growth factor receptor (EGFR), 14,25,26 insulin-like growth factor-1 receptor (IGF1R), 14,27 and plateletderived growth factor receptor a (PDGFRa) 6,28,29 have been proven responsible for Akt/mTOR pathway activation in SS, and some preclinical studies have lent credence to targeting this pathway.…”

“…1,2 Therefore, the Akt/mTOR pathway is regarded as oncogenic and has the potential to be a therapeutic target. Several previous studies have demonstrated activation of the Akt/mTOR pathway and its contribution to cell survival and proliferation in SS cell lines [3][4][5][6] as well as the effects of the clinical application of therapeutic agents targeting mTOR in soft tissue sarcoma (STS). 7 The prognostic impact of the activation of this pathway, however, remains to be clarified.…”

Baicalin Induces Apoptosis in Leukemia HL-60/ADR Cells via Possible Down-regulation of the PI3K/Akt Signaling Pathway

“…Studies have shown that it plays a key role in the inhibition of cell apoptosis and the promotion of cell proliferation by affecting the activation state of a variety of downstream effector molecules. It is closed related to the occurrence and development of many human tumors including hematological malignancies (Xu et al, 2003;Friedrichs et al, 2011;Sun et al, 2011). Akt is a potent kinase for bad as a member of the Bcl-2 family.…”