The interaction between the Wnt/β-catenin signaling cascade and PKG activation in cancer

The activation of the Wnt/β-catenin signaling cascade has been well studied and documented in colorectal cancer（CRC）.The long-term use of non-steroidal anti-inflammatory drugs（NSAIDs） has been shown to reduce the incidence and risk of death from CRC in numerous epidemiological studies.The NSA1 D sulindac has also been reported to cause regression of precancerous adenomas in individuals with familial adenomatous polyposis who are at high risk of developing CRC.The mechanism responsible for cancer chemopreventive activity of NSAIDs is not well understood but may be unrelated to their cyclooxygenase inhibitory activity.Emerging evidence suggests that sulindac inhibits the growth of colon tumor cells by suppressing the activity of certain phosphodiesterase isozymes to activate cGMβ-dependent protein kinase,PKG,through the elevation of the second messenger cyclic guanosine monophosphote,cGMP.PKG activation has been shown to inhibit the nuclear translocation of β-catenin,reduce β-catenin mRNA and protein levels,and suppress the transcriptional activity of β-catenin.This review describes the relationship between the Wnt/β-catenin signaling cascade and the activation of PKG through PDE inhibition and elevation of intracellular cGMP levels.

基于美国研究生培养模式探讨中医药院校创新型研究生的培养

研究生教育是我国培养高层次人才的主要方式,也是创新型人才培养的主要途径。文章通过分析美国研究生培养模式,结合我国中医院校研究生培养的特点,从研究生质量问题、研究生课程和教学以及研究生导师情况等方面为切入点来解决培养创新型研究生的问题,改善我国创新型研究生培养模式,提高研究生培养质量。

Sulindac sulfide selectively increases sensitivity of ABCC1 expressing tumor cells to doxorubicin and glutathione depletion

ATP-binding cassette（ABC） transporters ABCC1（MRP1）,ABCB1（P-gp）,and ABCG2（BCRP） contribute to chemotherapy failure.The primary goals of this study were to characterize the efficacy and mechanism of the nonsteroidal anti-inflammatory drug（NSAID）,sulindac sulfide,to reverse ABCC1 mediated resistance to chemotherapeutic drugs and to determine if sulindac sulfide can influence sensitivity to chemotherapeutic drugs independently of drug efflux.Cytotoxicity assays were performed to measure resistance of ABC-expressing cell lines to doxorubicin and other chemotherapeutic drugs.NSAIDs were tested for the ability to restore sensitivity to resistance selected tumor cell lines,as well as a large panel of standard tumor cell lines.Other experiments characterized the mechanism by which sulindac sulfide inhibits ABCC1 substrate and co-substrate（GSH） transport in isolated membrane vesicles and intact cells.Selective reversal of multi-drug resistance（MDR）,decreased efflux of doxorubicin,and fluorescent substrates were demonstrated by sulindac sulfide and a related NSAID,indomethacin,in resistance selected and engineered cell lines expressing ABCC 1,but not ABCB 1 or ABCG2.Sulindac sulfide also inhibited transport of leukotriene C_4 into membrane vesicles.Sulindac sulfide enhanced the sensitivity to doxorubicin in 24 of 47 tumor cell lines,including all melanoma lines tested（7-7）.Sulindac sulfide also decreased intracellular GSH in ABCC1 expressing cells,while the glutathione synthesis inhibitor,BSO,selectively increased sensitivity to sulindac sulfide induced cytotoxicity.Sulindac sulfide potently and selectively reverses ABCC1-mediated MDR at clinically achievable concentrations.ABCC1 expressing tumors may be highly sensitive to the direct cytotoxicity of sulindac sulfide,and in combination with chemotherapeutic drugs that induce oxidative stress.

EGFR signaling promotes resistance to CHK1 inhibitor prexasertib in triple negative breast cancer

Aim:Innate resistance to the CHK1 inhibitor prexasertib has been described,but resistance mechanisms are not understood.We aimed to determine the role epidermal growth factor receptor(EGFR)plays in innate resistance to prexasertib in triple negative breast cancer(TNBC).Methods:Using a panel of pre-clinical TNBC cell lines,we measured the sensitivity to prexasertib.We examined the effect activation of EGFR had on prexasertib sensitivity.We measured the synergy of dual blockade of EGFR with erlotinib and CHK1 with prexasertib in TNBC cell lines and xenografts.Results:EGFR overexpression and activation increased resistance to CHK1 inhibition by prexasertib.EGFR promoted the phosphorylation of BCL2-associated agonist of cell death(BAD),inactivating its pro-apoptotic functions.Inhibition of EGFR reversed BAD phosphorylation,increasing sensitivity to prexasertib.Conclusion:The use of prexasertib as a monotherapy in TNBC has been limited due to modest clinical responses.We demonstrated that EGFR activation contributes to innate resistance to prexasertib in TNBC and potentially other cancers.EGFR expression status should be considered in clinical trials examining prexasertib’s use as a monotherapy or combination therapy.

EGFR signaling promotes resistance to CHK1 inhibitor prexasertib in triple negative breast cancer

Aim:Innate resistance to the CHK1 inhibitor prexasertib has been described,but resistance mechanisms are not understood.We aimed to determine the role epidermal growth factor receptor(EGFR)plays in innate resistance to prexasertib in triple negative breast cancer(TNBC).Methods:Using a panel of pre-clinical TNBC cell lines,we measured the sensitivity to prexasertib.We examined the effect activation of EGFR had on prexasertib sensitivity.We measured the synergy of dual blockade of EGFR with erlotinib and CHK1 with prexasertib in TNBC cell lines and xenografts.Results:EGFR overexpression and activation increased resistance to CHK1 inhibition by prexasertib.EGFR promoted the phosphorylation of BCL2-associated agonist of cell death(BAD),inactivating its pro-apoptotic functions.Inhibition of EGFR reversed BAD phosphorylation,increasing sensitivity to prexasertib.Conclusion:The use of prexasertib as a monotherapy in TNBC has been limited due to modest clinical responses.We demonstrated that EGFR activation contributes to innate resistance to prexasertib in TNBC and potentially other cancers.EGFR expression status should be considered in clinical trials examining prexasertib’s use as a monotherapy or combination therapy.

BRD7 plays an anti-inflammatory role during early acute inflammation by inhibiting activation of the NF-кB signaling pathway

Increasing evidence has shown a strong association between tumor-suppressor genes and inflammation.However,the role of BRD7 as a novel tumor suppressor in inflammation remains unknown.In this study,by observing BRD7 knockout mice for 6–12 months,we discovered that compared with BRD7+/+mice,BRD7^(−/−)mice were more prone to inflammation,such as external inflammation and abdominal abscess.By using mouse embryo fibroblast(MEF)cells from the BRD7 knockout mouse,an in vitro lipopolysaccharide(LPS)-stimulated MEF cell line was established.The mRNA levels of interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),chemokine(C-X-C motif)ligand 1(CXCL-1)and inducible nitric oxide synthase(iNOS)were significantly increased in BRD7^(−/−)MEF cells compared with BRD7+/+MEF cells after LPS stimulation for 1 or 6 h.In addition,the cytoplasm-to-nucleus translocation of nuclear factor kappa-B(NF-κB;p65)and an increased NF-κB reporter activity were observed in BRD7^(−/−)MEF cells at the 1 h time point but not at the 6 h time point.Furthermore,an in vivo dextran sodium sulfate(DSS)-induced acute colitis model was created.As expected,the disease activity index(DAI)value was significantly increased in the BRD7^(−/−)mice after DSS treatment for 1–5 days,which was demonstrated by the presence of a significantly shorter colon,splenomegaly and tissue damage.Moreover,higher expression levels of IL-6,TNF-α,p65,CXCL-1 and iNOS,and an increased level of NF-κB(p65)nuclear translocation were also found in the DSS-treated BRD7^(−/−)mice.These findings suggest that BRD7 has an anti-inflammatory role during early acute inflammation by inhibiting activation of the NF-кB signaling pathway,which provides evidence to aid in understanding the therapeutic effects of BRD7 on inflammatory diseases.