7-Deoxynarciclasine shows promising antitumor efficacy by targeting Akt against hepatocellular carcinoma

Akt is a promising therapeutic target for cancer treatment. In our study, we have identified that 7-deoxynarciclasine (7-DONCS) is a potential inhibitor of Akt, which results in the repression of multiple oncogenic processes in hepatocellular carcinoma (HCC). We have found that 7-DONCS suppresses the growth of HCC by inducing the apoptotic and autophagic capacities, as well as by inhibiting epithelial–mesenchymal transition (EMT) in vitro and in vivo. Pretreatment of cells with specific autophagy inhibitor (Bafilomycin A1) or knockdown of endogenous LC-3B by siRNA strongly abrogates 7-DONCS-regulated apoptosis and EMT. Consequently, we have found that 7-DONCS selectively inhibits phospho-Akt (Ser473), and subsequent molecular docking reveals that 7-DONCS directly binds to the C-terminal domain of Akt. Overexpressing Akt significantly blocks these effects via 7-DONCS in HCC cells. Furthermore, 7-DONCS, by targeting Akt, exhibits a promising therapeutic effect in orthotopic hepatocellular tumors. Finally, higher p-Akt expression is associated with poor prognosis, and higher level of Akt was positively correlated with the enrichment of both apoptosis and autophagy downregulation, and EMT upregulation in HCC patients. These studies suggest that 7-DONCS serves as an attractive drug candidate by targeting Akt for future HCC therapy.     

PI3K/Akt signalling pathway and cancer

Phosphatidylinositol-3 kinases, PI3Ks, constitute a lipid kinase family characterized by their ability to phosphorylate inositol ring 3'-OH group in inositol phospholipids to generate the second messenger phosphatidylinositol-3,4,5-trisphosphate (PI-3,4,5-P(3)). RPTK activation results in PI(3,4,5)P(3) and PI(3,4)P(2) production by PI3K at the inner side of the plasma membrane. Akt interacts with these phospholipids, causing its translocation to the inner membrane, where it is phosphorylated and activated by PDK1 and PDK2. Activated Akt modulates the function of numerous substrates involved in the regulation of cell survival, cell cycle progression and cellular growth. In recent years, it has been shown that PI3K/Akt signalling pathway components are frequently altered in human cancers. Cancer treatment by chemotherapy and gamma-irradiation kills target cells primarily by the induction of apoptosis. However, the development of resistance to therapy is an important clinical problem. Failure to activate the apoptotic programme represents an important mode of drug resistance in tumor cells. Survival signals induced by several receptors are mediated mainly by PI3K/Akt, hence this pathway may decisively contribute to the resistant phenotype. Many of the signalling pathways involved in cellular transformation have been elucidated and efforts are underway to develop treatment strategies that target these specific signalling molecules or their downstream effectors. The PI3K/Akt pathway is involved in many of the mechanisms targeted by these new drugs, thus a better understanding of this crossroad can help to fully exploit the potential benefits of these new agents.     

TTI1 promotes non-small-cell lung cancer progression by regulating the mTOR signaling pathway

The role of TELO2-interacting protein 1 (TTI1) in the progression of several types of cancer has been reported recently. The aim of this study was to estimate the expression and potential value of TTI1 in non-small-cell lung cancer (NSCLC) patients. The expression of TTI1 and its prognostic value in NSCLC from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database were analyzed. To verify the bioinformatics findings, a tissue microarray containing 160 NSCLC and paired peritumoral tissues from NSCLC patients was analyzed by immunohistochemistry for TTI1. Subsequently, the roles of TTI1 in NSCLC cells were investigated in vivo by establishing xenograft models in nude mice and in vitro by transwell, CCK-8, wound healing, and colony formation assays. In addition, quantitative real-time polymerase chain reaction and western blot were applied to explore the underlying mechanism by which TTI1 promotes tumor progression. Finally, the relationship between TTI1 and Ki67 expression level in NSCLC was probed, and Kaplan–Meier and Cox analyses were performed to assess the prognostic merit of TTI1 and Ki67 in NSCLC patients. We found that the expression of TTI1 was significantly upregulated in NSCLC tissues compared to paired peritumoral tissues, which coincides with the bioinformatics findings from the TCGA and GEO databases. TTI1 was highly expressed in NSCLC patients with large tumors, advanced tumor stage, and lymphatic metastasis. In addition, the prognostic analysis identified TTI1 as an independent indication for poor prognosis of NSCLC patients. In vitro, upregulation of TTI1 in NSCLC cells could facilitate cell invasion, metastasis, viability, and proliferation. Mechanistically, our study verified that TTI1 could regulate mTOR activity, which has a pivotal role in human cancer. Consistently, the expressions of TTI1 and Ki67 had a positive relationship in NSCLC cells and tissues. Notably, patients with overexpression of TTI1 or Ki67 had a shorter overall survival rate and a higher disease-free survival rate compared to patients with low expression of TTI1 or Ki67, and the combination of TTI1 and Ki67 was an independent parameter predicting the prognosis and recurrence of NSCLC patients. We conclude that TTI1 promotes NSCLC cell proliferation, metastasis, and invasion by regulating mTOR activity, and the combination of TTI1 and Ki67 is a valuable molecular biomarker for the survival and recurrence of NSCLC patients.     

EPHA3 regulates the multidrug resistance of small cell lung cancer via the PI3K/BMX/STAT3 signaling pathway

Tumor Biology - Multidrug resistance (MDR) is a major obstacle to the treatment of small cell lung cancer (SCLC). EPHA3 has been revealed to be the most frequently mutated Eph receptor gene in lung...     

IL-6/STAT3信号传导通路及其在肿瘤靶向治疗中的作用

白细胞介素-6(IL-6)与肿瘤患者的分期、预后、转归以及对化疗药物的敏感性有关,且在患者的肿瘤组织及血清中常呈过表达.IL-6主要通过介导信号转换和转录激活因子3(STAT3)信号传导通路(IL-6/STAT3信号传导通路)来调节肿瘤细胞的增殖和分化.因此,IL-6/STAT3信号传导通路的阻断,对肿瘤具有潜在治疗意...     

Mesenchymal stem cells enhance lung cancer initiation through activation of IL-6/JAK2/STAT3 pathway

Background

The role of mesenchymal stem cells (MSCs) and IL-6 in lung cancer has not been well-addressed. We aimed to determine if MSCs can enhance the ability of tumor initiation of lung cancer cells, and link MSCs with activation of the IL-6/JAK2/STAT3 signaling pathway.

Materials and methods

Lung cancer cell lines A549 and CL1-5 were directly or indirectly cocultured with MSCs. Spheres were defined as cell colonies with >50% area showing 3-dimensional structure and blurred cell margins. Cells without and with MSCs were injected into NOD/SCID mice. The percentage of tumor formation was determined. The influence of the IL-6/JAK2/STAT3 signaling pathway in cancer cell sphere formation and tumor growth were investigated.

Results

A very small number of lung cancer cells, when mixed with otherwise non-tumorigenic MSCs, obtained de novo tumorigenicity when injected subcutaneously and allowed to form a tumor xenograft. Secretion of IL-6 from MSCs increased activation of the JAK2/STAT3 pathway in cancer cells, and enhanced sphere formation and tumor initiation. A reduced capacity of tumor formation of A549 and CL1-5 lung cancer cells when IL-6 was inhibited in MSCs or STAT3 was silenced in A549 and CL1-5 admixed with MSCs.

Conclusions

Culture of A549 or CL1-5 lung cancer cells with MSCs increased sphere formation, drug resistance, and overexpression of pluripotency markers through activation of the IL-6/JAK2/STAT3 pathway. MSCs enhanced the capability of A549 and CL1-5 lung cancer cells to form tumors in immunodeficient mice. Blockade of the IL-6/JAK2/STAT3 pathway attenuated the capability of A549 and CL1-5 cells to form tumors.     

人参皂苷Rg3胶囊联合化疗治疗中晚期非小细胞肺癌的疗效观察

目的观察人参皂苷Rg3对非小细胞肺癌患者血清VEGF水平及疗效的影响。方法选择ⅢB期不可手术切除的患者人组,实验组给予化疗同时口服Rg320mg,每日二次口服,用药2个疗程;对照组单纯给予化疗。用药结束后,观察患者血清VEGF、CEA水平变化情况,患者生活质量改善情况及毒副反应。结果用药2个疗程后,实验组患者血清VEGF水平明显下降为（315．7±15．2）pg／mL,CEA水平明显下降者占78％,生活质量KPs评分明显改善者为74．6％,毒副反应发生率明显减低,与对照组相比较均有显著性差异（P〈0．05）。结论对于ⅢB期不可手术切除非小细胞肺癌患者,给予化疗同时口服人参皂苷Rg3治疗,可抑制肿瘤新生血管的形成,增加抑瘤效果,改善患者生活质量。     

MiR-613 induces cell cycle arrest by targeting CDK4 in non-small cell lung cancer

Background

Deregulation of microRNAs (miRNAs) has been associated with a variety of cancers, including non-small cell lung cancer (NSCLC). Here, we investigated anomalous miR-613 expression and its possible functional consequences in primary NSCLC samples and NSCLC-derived cell lines.

Methods

The expression of miR-613 was measured by quantitative RT-PCR in 56 primary NSCLC tissues and adjacent non-tumor tissues. The effect of miR-613 up- or down-regulation in NSCLC-derived cells was evaluated in vitro by cell viability and colony formation assays and in vivo by growth assays in xenografted nude mice.

Results

Using quantitative RT-PCR, we found that miR-613 was down-regulated in 76.8 % (43/56) of the primary NSCLC tissues tested when compared to the adjacent non-tumor tissues. We also found that the miR-613 mimic used reduced in vitro cell viability and colony formation by inducing cell cycle arrest in NSCLC-derived cells, and inhibited in vivo tumor cell growth in xenografted nude mice. Inversely, we found that the miR-613 inhibitor used increased the viability and colony forming capacity of NSCLC-derived cells and tumor cell growth in xenografted nude mice. In addition, we identified CDK4 as a potential target of miR-613 using in silico Miranda predictions. Subsequent dual-luciferase reporter assays revealed that CDK4 acts as a direct target of miR-613. Concordantly, we found that both miR-613 mimics and inhibitors could decrease and increase CDK4 protein levels in NSCLC-derived cells, respectively.

Conclusions

From our results we conclude that miR-613 may act as a tumor suppressor in NSCLC and may serve as a tool for miRNA-based NSCLC therapy.

     

Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines

Autophagy is an evolutionarily conserved survival pathway in eukaryote and is frequently upregulated in cancer cells after chemotherapy or targeted therapy. Thus induction of autophagy has emerged as a drug resistance mechanism. In this study, we found that crizotinib induced a high level of autophagy in lung cancer cells through inhibition of STAT3. Ectopic expression of wild-type or constitutive activated STAT3 significantly suppressed the effect of crizotinib on autophagy. Interestingly, crizotinib-mediated inhibition of STAT3 is in a step-wise manner. Firstly it inhibited cytoplasmic STAT3, which leads to the phosphorylation of EIF2A, then inhibited nuclear STAT3, which leads to the downregulation of BCL-2. Cell death induced by crizotinib was greatly enhanced after the inhibition of autophagy by the pharmacological inhibitors or shRNAs against Beclin-1. Moreover, the autophagy inhibitor HCQ significantly augmented the anti-tumor effect of crizotinib in a mouse xenograft model. In conclusion, crizotinib can induce cytoprotective autophagy by suppression of STAT3 in lung cancer cells. Thus, autophagy inhibition represents a promising approach to improve the efficacy of crizotinib in the treatment of targeted lung cancer patients.     

Targeting the HGF/Met signalling pathway in cancer

Under normal conditions, hepatocyte growth factor (HGF)-induced Met tyrosine kinase (TK) activation is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, and ligand activated receptor internalisation and degradation. Despite these controls, HGF/Met signalling contributes to oncogenesis and tumour progression in several cancers and promotes aggressive cellular invasiveness that is strongly linked to tumour metastasis. The prevalence of HGF/Met pathway activation in human malignancies has driven rapid growth in cancer drug development programmes. Pathway inhibitors can be divided broadly into biologicals and low molecular weight synthetic TK inhibitors; of these, the latter now outnumber all other inhibitor types. We review here the basic properties of HGF/Met pathway antagonists now in preclinical and clinical development as well as the latest clinical trial results. The main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment include optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of optimal therapy combinations. The wealth of basic information, analytical reagents and model systems available concerning HGF/Met oncogenic signalling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective disease control.