ETS variant transcription factor 6 (ETV6)neurotrophic receptor tyrosine kinase 3 (NTRK3) (EN) fusions are typically found in rare diseases, such as primary renal fibrosarcoma (only six cases have been reported), secretory carcinoma of the breast and salivary gland (1 case), and AML (4 cases). Few cases have been reported, and expression of the EN gene fusion requires additional clinical data and fundamental research to be supported. The aim of the present study was to determine the inhibitory effect of Andrographis paniculata methanol extract (MeAP) on EN-related cell lines, IMS-M2 and BaF3/EN, as well as evaluate the mechanism of action. Vero cells were used as control cells. Trypan blue staining and MTT were used to evaluate the inhibitory effect of MeAP on tested cells. Western blotting and immunoprecipitation were used to detect the activation of EN after MeAP treatment. The IC 50 values of MeAP were found to be 12.38±0.57 µg/ml (IMS-M2) and 13.06±0.49 µg/ml (BaF3/EN). MeAP was observed to inhibit cell proliferation in a time, dose, and cell density-dependent manner. The IC 50 value for MeAP in Vero cells was markedly higher, at 109.97±4.24 (µg/ml), indicating a much less sensitive effect. Furthermore, MeAP treatment inhibited EN phosphorylation and induced apoptosis in these cells. Collectively, the present study demonstrated that MeAP has an oncogenic effect on EN fusion-positive cell lines, in particular.
Insulin receptors (IRs) belong to the large class of tyrosine kinase receptors and are activated by insulin, IGF-I, IGF-II and. The binding of ligands to the IR initiates a cascade of events leading to activation of signal transduction pathways, mainly PI3K and AKT pathways, and induce glucose uptake and cell proliferation. IR signaling pathway has been reported to be deregulated in cancer cells resulting in a range of clinical manifestations including cancer. It has been shown that the presence of IR was required for transformation induced by many oncogenes and over-expression or constitutive activation of IR gave rise to transformed phenotypes. Here, we report an unexpected role of a tumor suppressor tristetraprolin (TTP) in inhibiting IR. TTP bound to the AU-rich element (ARE) within the mRNA 3′UTRs of IR, enhanced the decay of their mRNAs and inhibited the metabolism of cancer cells. The ectopic expression of IR without their 3′UTRs blocked the inhibitory effects of TTP on the Warburg effect cancer. Our data propose a new model whereby the TTP down-regulates IR and plays an important role as a negative regulator of both the energy metabolism and proliferation of cancer cells. Citation Format: Ji Eun Yoon, VO MAI TRAM, Nal Ae Yoon, Jin Ho Back, Young Joo Min, Wha Ja Cho. TTP inhibits insulin receptor signals in cancer cell. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1170. doi:10.1158/1538-7445.AM2015-1170
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