Fluoxetine induces cytotoxic endoplasmic reticulum stress and autophagy in triple negative breast cancer

AIM: To investigate the mechanism of action of lipophilic antidepressant fluoxetine(FLX) in representative molecular subtypes of breast cancer.METHODS: The anti-proliferative effects and mechanistic action of FLX in triple-negative(SUM149PT) and luminal(T47D and Au565) cancer cells and nontransformed MCF10 A were investigated. Reverse phase protein microarray(RPPM) was performed with and without 10 μmol/L FLX for 24 and 48 h to determine which proteins are significantly changed. Viability and cell cycle analysis were also performed to determine drug effects on cell growth. Western blotting was used to confirm the change in protein expression examined by RPPM or pursue other signaling proteins. RESULTS: The FLX-induced cell growth inhibition in all cell lines was concentration- and time-dependent but less pronounced in early passage MCF10 A. In comparison to the other lines,cell growth reduction in SUM149 PT coincided with significant induction of endoplasmic reticulum(ER) stress and autophagy after 24 and 48 h of 10 μmol/L FLX,resulting in decreased translation of proteins along the receptor tyrosine kinase/Akt/mammalian target of rapamycin pathways. The increase in autophagy marker,cleaved microtubule-associated protein 1 light chain 3,in SUM149 PT after 24 h of FLX was likely due to increased metabolic demands of rapidly dividing cells and ER stress. Consequently,the unfolded protein response mediated by double-stranded RNA-dependent protein kinase-like ER kinase resulted in inhibition of protein synthesis,growth arrest at the G1 phase,autophagy,and caspase-7-mediated cell death.CONCLUSION: Our study suggests a new role for FLX as an inducer of ER stress and autophagy,resulting in death of aggressive triple negative breast cancer SUM149 PT.

Molecular Insights on the Transition of Non-invasive DCIS to Invasive Ductal Carcinoma

More than 90% of breast cancer-related deaths are caused by metastasis not primary tumor. To effectively reduce cancer mortality, it is extremely important to predict the risk of, and to intervene in, the critical transition from

miR-7/TGF-β2 axis sustains acidic tumor microenvironment-induced lung cancer metastasis

Acidosis,regardless of hypoxia involvement,is recognized as a chronic and harsh tumor microenvironment(TME)that educates malignant cells to thrive and metastasize.Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression,the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy.Here,chemical-induced and transgenic mouse models for colon,liver and lung cancer were established,respectively.miR-7 and TGF-β2 expressions were examined in clinical tissues(n=184).RNA-seq,miRNA-seq,proteomics,biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis.Our data show that lung cancer is sensitive to the increased acidification of TME,and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5 p.TGF-β2 is a direct target of miR-7-5 p.The reduced expression of miR-7-5 p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer.Indeed,overexpression of miR-7-5 p reduces the acidic p H-enhanced lung cancer metastasis.Furthermore,the human lung tumor samples also show a reduced miR-7-5 p expression but an elevated level of activated TGF-β2;the expressions of both miR-7-5 p and TGF-β2 are correlated with patients’survival.We are the first to identify the role of the miR-7/TGF-β2 axis in acidic p H-enhanced lung cancer metastasis.Our study not only delineates how acidification directly affects tumorigenesis,but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer(NSCLC)treatment.Our study opens an avenue to explore the p H-sensitive subcellular components as novel therapeutic targets for cancer treatment.

天津高银117大厦新型抗侧移模块化低位顶升钢平台模架体系安装施工关键技术

天津高银117大厦塔楼核心筒施工具有体量大(单层面积最大为1072 m^(2))、结构高度高(结构施工高度为596.2 m)、层高变化多(共计20余种层高)、墙体分段、厚度及立面变化多(外墙厚度由1400 mm分次内收至300 mm),劲性柱构件较多等诸多施工难点。为了保证工程施工进度与质量,综合国内外多种模架形式,最终选用了抗侧移模块化低位顶升钢平台模架体系进行核心筒施工,并对其设计原理及组成、安装施工工艺流程及操作要点等开展了研究。研究内容及结论包括:1)顶模体系由钢平台系统、支撑与顶升系统、挂架与围护系统、模板系统及抗侧装置五部分组成,各部分均需满足超高层施工安全、快捷的要求及自身强度、刚度等性能要求。2)为适应层高的变化,模板系统按标准层高配置定型模板,模板立面位置在模架体系固定时可自行进行调节,核心筒内收处模板需按结构进行调节;层高变化较大时,支撑立柱增加非标准节进行调节;采用大行程的液压油缸满足不同层高的顶升高度要求。3)为了方便核心筒内钢构件的吊装,钢平台留设钢板、劲性柱吊装孔,对于一次性不能就位的钢板设置水平滑道,水平滑动至安装部位;立柱的高度选择满足最大吊装分段的要求。4)根据工程总体施工部署,核心筒施工完4层夹层结构以后,首先安装塔吊,待塔吊安装完成即插入顶模安装,计划30 d安装、调试完毕。5)顶模安装总体流程为:测量放线→下箱梁吊装→液压油缸吊装→上箱梁吊装→支撑立柱吊装→钢平台桁架安装→挂架及围护系统安装→模板系统安装→抗侧装置安装。6)装配式钢桁架平台桁架的安装方法是:“地面拼装、空中组对”,即平台桁架在制作厂预拼装成短片、运输到现场后,再在地面拼装成榀,然后吊装到空中组对、栓接。内外挂架在地面拼成单元,然后分片或分块吊装。经天津高银117大厦应用实践证明,该顶模体系具有支撑立柱高,可同时进行钢板剪力墙全工艺流程竖向流水施工,抵抗风致侧移能力强等独特优点,达到了5 d一层的施工速度,创造了良好的经济和社会效益。