Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have demonstrated clinical benefits in the treatment of several tumour types. However, the emergence of TKI resistance restricts the therapeutic effect. This study uses non-small cell lung cancer (NSCLC) to explore the mechanisms contributing to TKI resistance in tumours. METHODS: Biological phenotypes and RNA microarray expression data were analysed in NSCLC cells with and without TKI pretreatment. Specific inhibitors and siRNAs were used to validate the direct involvement of an AKT/FOXM1/STMN1 pathway in TKI resistance. Patients' tissues were analysed to explore the clinical importance of FOXM1 and STMN1. RESULTS: In vitro and in vivo studies showed that TKIs induced the enrichment of cancer stem cells (CSC), promoted epithelial to mesenchymal transition (EMT), and conferred multidrug resistance on NSCLC cells in a cell type- and TKI class-dependent manner. Mechanistically, TKIs activated an AKT/FOXM1/STMN1 pathway. The crucial role of this pathway in TKI-induced enrichment of CSC and drug resistance was verified by silencing FOXM1 and STMN1 or blocking the AKT pathway. Additionally, overexpression of STMN1 was associated with upregulation of FOXM1 in advanced NSCLC patients, and STMN1/FOXM1 upregulation predicted a poor outcome. CONCLUSIONS: Our findings elucidate an additional common mechanism for TKI resistance and provide a promising therapeutic target for reversing TKI resistance in NSCLC.

The fear gene stathmin alleles generated heterosis on feed efficiency parameters in Peking ducks.

Stathmin is an inhibitor of microtubule formation, as highly expressed in the lateral nucleus (LA) of the amygdala as well as in the thalamic and cortical structures that send information to the LA about the learned and innate fear. So we assume that STMN1 genetic variation may also affect the physical activity so as to influence the Residual Feed Intake (RFI) of duck. The Single Nucleotide Polymorphisms (SNPs) in duck Stathmin gene were screened by sequencing and genotyped by restriction endonuclease Msp I, EcoR I, Xho I, Taq I, EcoR II. A total of five SNPs (c.187 -15G > A, c.187 -110T > C, c.379 -95G > A, c.379 -318C > T, c.426 C > T) were detected in duck STMN1 gene. The c.187 -15G > A is near the 3' splice site of intron 2, which has a putative effect on the STMN1 pre-mRNA secondary structures. The c.187 -15G > A genotypes had significant effect on RFI of Peking drakes (P < 0.01). Individuals with heterozygous genotypes were more productive than that with homozygous genotypes, which suggested a molecular heterosis in c.187 -15 alleles on RFI. The current study is the first step to confirm the relationship between STMN1 gene polymorphisms and RFI. Supplemental material is available for this article. Go to the publisher's online edition of Animal Biotechnology for a figure of linkage disequilibrium between SNPs and table about frequencies of haploype.

[Effect of gallnut extract on nasopharyngeal carcinoma 5-8F cells and its mechanism].

OBJECTIVE: To determine the biological activity of ellagic acid extracted from gallnut against nasopharyngeal carcinoma and its molecular mechanism. METHODS: Nasopharyngeal carcinoma 5-8F cells were treated with 2, 4, 6 µg/mL ellagic acid for 48 h in vitro. The cell proliferation and cell apoptosis were analyzed by MTT and Hoechst33258 stain. The cell cycle and protein expression were measured by flow cytometry and Western blot. RESULTS: Ellagic acid inhibited the proliferation of 5-8F cells. The inhibition rates were (29.35±4.95)%, (53.32 ±4.44)% and ( 61.75 + 6.93)%, respectively, with significant difference from the control group (P<0.01). S phase cells in the experimental groups were (25.47±0.74)%, (28.08±1.41)% and (35.49±0.66)%, respectively, with significant difference (P<0.01) from the control group (21.26±0.70)%. Cells in the experimental groups showed nuclear pyknosis, karyorrhexis and poptotic cell morphology. The expression of COX-2 and stathmin in 5-8F cells was down-regulated with increased drug concentration. CONCLUSION: Ellagic acid extracted from gallnut has activity against nasopharyngeal carcinoma cells, and its mechanism may be related to down-regulated expression of COX-2 and stathmin.

stathmin, a gene enriched in the amygdala, controls both learned and innate fear.

Little is known about the molecular mechanisms of learned and innate fear. We have identified stathmin, an inhibitor of microtubule formation, as highly expressed in the lateral nucleus (LA) of the amygdala as well as in the thalamic and cortical structures that send information to the LA about the conditioned (learned fear) and unconditioned stimuli (innate fear). Whole-cell recordings from amygdala slices that are isolated from stathmin knockout mice show deficits in spike-timing-dependent long-term potentiation (LTP). The knockout mice also exhibit decreased memory in amygdala-dependent fear conditioning and fail to recognize danger in innately aversive environments. By contrast, these mice do not show deficits in the water maze, a spatial task dependent on the hippocampus, where stathmin is not normally expressed. We therefore conclude that stathmin is required for the induction of LTP in afferent inputs to the amygdala and is essential in regulating both innate and learned fear.