Apoptosis In Lung Cancer Cells Research Articles

Long Non-Coding RNA POU5F1B Promotes the Occurrence and Development of Non-Small Cell Lung Cancer

The study aimed to investigate the expression level of POU5F1B in non-small cell lung cancer (NSCLC) patients’ serum, tissues, and cell lines and to identify its potential molecular mechanism in NSCLC pathogenesis. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was employed to detect POU5F1B expression. The associations between POU5F1B expression and age, gender, body mass index (BMI), smoking, tumor-node-metastasis (TNM) stage, type of tissues, and lymph node metastasis were analyzed. Furthermore, changes in the proliferation and apoptosis of lung cancer cells were observed after down-regulation of POU5F1B. The results demonstrated a significant increase in POU5F1B expression in NSCLC serum and cancer tissues with lymph node metastasis as well as in lung cancer cell lines. POU5F1B expression was found to be related to TNM stage, smoking, and lymph node metastasis in NSCLC patients and was an independent risk factor that affected NSCLC prognosis. Knockdown of POU5F1B reduced lung cancer cell proliferation and increased apoptosis activity. These findings suggest that POU5F1B promotes NSCLC development by promoting cell proliferation and inhibiting apoptosis.

Xanthatin induce DDP-resistance lung cancer cells apoptosis through regulation of GLUT1 mediated ROS accumulation.

Chemoresistance to cisplatin (DDP) therapy is a major obstacle that needs to be overcome in treating lung cancer patients. Xanthatin has been reported to exhibit an antitumor effect on various cancers, but the function of xanthatin in DDP-resistance lung cancer remains unclear. The study aimed to explore the effect and mechanisms of xanthatin on proliferation, apoptosis, and migration in DDP-resistance lung cancer cells. In the present study, xanthatin suppresses the expression of glucose transporter 1 (GLUT1), attenuates the pentose phosphate pathway (PPP), and causes ROS accumulation and apoptosis, thereby mitigating the antioxidative capacity in DDP-resistance cells. Previous studies have shown that GLUT1 is associated with resistance to platinum drugs. We found that GLUT1 was significantly increased in the DDP-resistant lung cancer cell line compared to the parental cell line, and xanthatin significantly downregulated GLUT1 expression in DDP-resistant lung cancer cells. Notably, overexpression of GLUT1 significantly reduced the production of ROS and increased cellular NADPH/NADP+ and GSH/GSSG ratios. Thus, these results suggest that xanthatin induces DDP-resistance lung cancer cells apoptosis through regulation of GLUT1-mediated ROS accumulation. These findings might provide a possible strategy for the clinical treatment of DDP-resistant lung cancer.

Patchouli alcohol induces G0 /G1 cell cycle arrest and apoptosis in vincristine-resistant non-small cell lung cancer through ROS-mediated DNA damage.

Lung cancer, especially non-small cell lung cancer (NSCLC), is one of the leading causes of cancer-related deaths worldwide. Vincristine (VCR) is a chemotherapeutic agent for lung cancers; however, its effectiveness is limited by side effects and the development of drug resistance. Patchouli alcohol (PA), from Pogostemon cablin extract, is known to possess anti-inflammatory and anticancer properties. In this study, we investigated the role of PA in inducing reactive oxygen species (ROS)-mediated DNA damage in A549 and VCR-resistant A549/V16 NSCLC cells. The anticancer potential of PA was studied using the MTT assay, colony formation, flow cytometry analysis, western blotting, DCFDA staining, immunofluorescence staining, and TUNEL assay techniques. The intracellular ROS levels were enhanced in PA-treated cells, activating the CHK1 and CHK2 signaling pathways. PA further inhibited proliferation and colony-forming abilities and induced cell cycle arrest at the G0 /G1 phase by regulating p53/p21 and CDK2/cyclin E1 expression. Moreover, PA increased the percentage of cells in the subG1 phase and induced apoptosis by activating the Bax/caspase-9/caspase-3 intrinsic pathway. In addition, drug resistance (p-glycoprotein) and cancer stem cell (CD44 and CD133) markers were downregulated after PA treatment. Furthermore, combining PA and cisplatin exhibited synergistic inhibitory activity in A549 and A549/V16 cells. PA induced ROS-mediated DNA damage, triggered cell cycle arrest and apoptosis, attenuated drug resistance and cancer stem cell phenotypes, and synergistically inhibited proliferation in combination with cisplatin. These findings suggest that PA has the potential to be used for the treatment of NSCLC with or without VCR resistance.

3-Deoxysappanchalcone Inhibits Cell Growth of Gefitinib-Resistant Lung Cancer Cells by Simultaneous Targeting of EGFR and MET Kinases.

The mechanistic functions of 3-deoxysappanchalcone (3-DSC), a chalcone compound known to have many pharmacological effects on lung cancer, have not yet been elucidated. In this study, we identified the comprehensive anti-cancer mechanism of 3-DSC, which targets EGFR and MET kinase in drug-resistant lung cancer cells. 3-DSC directly targets both EGFR and MET, thereby inhibiting the growth of drug-resistant lung cancer cells. Mechanistically, 3-DSC induced cell cycle arrest by modulating cell cycle regulatory proteins, including cyclin B1, cdc2, and p27. In addition, concomitant EGFR downstream signaling proteins such as MET, AKT, and ERK were affected by 3-DSC and contributed to the inhibition of cancer cell growth. Furthermore, our results show that 3-DSC increased redox homeostasis disruption, ER stress, mitochondrial depolarization, and caspase activation in gefitinib-resistant lung cancer cells, thereby abrogating cancer cell growth. 3-DSC induced apoptotic cell death which is regulated by Mcl-1, Bax, Apaf-1, and PARP in gefitinib-resistant lung cancer cells. 3-DSC also initiated the activation of caspases, and the pan-caspase inhibitor, Z-VAD-FMK, abrogated 3-DSC induced-apoptosis in lung cancer cells. These data imply that 3-DSC mainly increased mitochondria-associated intrinsic apoptosis in lung cancer cells to reduce lung cancer cell growth. Overall, 3-DSC inhibited the growth of drug-resistant lung cancer cells by simultaneously targeting EGFR and MET, which exerted anti-cancer effects through cell cycle arrest, mitochondrial homeostasis collapse, and increased ROS generation, eventually triggering anticancer mechanisms. 3-DSC could potentially be used as an effective anti-cancer strategy to overcome EGFR and MET target drug-resistant lung cancer.

The effects of epirubicin-loaded Boc-L-Diphenylalanine peptide nanoparticles on cytotoxicity, genotoxicity, oxidative stress, and apoptosis in non-small cell lung cancer cells.

Peptides, which are important components of the human body, appear in different chemistry applications. Perhaps the most important of these applications is the use of these structures in drug delivery systems due to their biocompatibility properties. Diphenylalanine (FF) peptide-based systems, which are part of the ß-amyloid polypeptide sequence and are known as the smallest dipeptide group, are particularly preferred due to their biocompatible nature, thermal stability, high ionic strength in water in new targeted drug systems. Epirubicin, the epimer of doxorubicin, is utilized in treating lung cancer. The side effects and the applied doses of epirubicin are being tried to be reduced. Therefore, in this study, epirubicin-loaded tert-butyloxycarbonyl protected diphenylalanine (Boc)-FF particles were synthesized and characterized and the effects of these peptides on cytotoxicity, genotoxicity, oxidative stress and apoptosis on non-small cell lung cancer cells (NSCLC) (A549) were evaluated. According to the results of the study, it was determined that epirubicin-loaded Boc-FF dipeptides significantly reduced the viability, oxidative stress, and increased DNA damage and apoptosis in the cells. The study suggests that epirubicin-loaded Boc-FF particles can be used as an alternative drug carrier for NSCLC treatment due to their physiological, chemical, and biological activity.

High expression of MYH9 inhibits apoptosis of non-small cell lung cancer cells through activating the AKT/c-Myc pathway

To investigate the role of myosin heavy chain 9 (MYH9) in regulation of cell proliferation, apoptosis, and cisplatin sensitivity of non-small cell lung cancer (NSCLC). Six NSCLC cell lines (A549, H1299, H1975, SPCA1, H322, and H460) and a normal bronchial epithelial cell line (16HBE) were examined for MYH9 expression using Western blotting. Immunohistochemical staining was used to detect MYH9 expression in a tissue microarray containing 49 NSCLC and 43 adjacent tissue specimens. MYH9 knockout cell models were established in H1299 and H1975 cells using CRISPR/Cas9 technology, and the changes in cell proliferation cell were assessed using cell counting kit-8 (CCK8) and clone formation assays; Western blotting and flow cytometry were used to detect apoptosis of the cell models, and cisplatin sensitivity of the cells was evaluated using IC50 assay. The growth of tumor xenografts derived from NSCLC with or without MYH9 knockout was observed in nude mice. MYH9 expression was significantly upregulated in NSCLC (P < 0.001), and the patients with high MYH9 expression had a significantly shorter survival time (P=0.023). In cultured NSCLC cells, MYH9 knockout obviously inhibited cell proliferation (P < 0.001), promoted cell apoptosis (P < 0.05), and increased their chemosensitivity of cisplatin. In the tumor-bearing mouse models, the NSCLC cells with MYH9 knockout showed a significantly lower growth rate (P < 0.05). Western blotting showed that MYH9 knockout inactivated the AKT/c- Myc axis (P < 0.05) to inhibit the expression of BCL2- like protein 1 (P < 0.05), promoted the expression of BH3- interacting domain death agonist and the apoptosis regulator BAX (P < 0.05), and activated apoptosis-related proteins caspase-3 and caspase-9 (P < 0.05). High expression of MYH9 contributes to NSCLC progression by inhibiting cell apoptosis via activating the AKT/c-Myc axis.

Vascular endothelial-derived Von Willebrand factor inhibits lung cancer progression through the αvβ3/ERK1/2 axis

Lung cancer remains a common malignant tumor causing death due to the rapid industrialization and serious pollution of the environment. The Von Willebrand Factor (vWF) protein is an endothelial marker and is widely used to diagnose cancer and other inflammations, however its exact mechanism of action remains largely unexplored. In particular, how it plays two opposing roles in tumor development is not clear. Our study aimed to the impact of endothelial-derived vWF on tumor development by co-culturing human umbilical vein endothelial cells (HUVECs) with lung cancer cells (95D and A549). A knockdown of endothelial-derived vWF assisted lung cancer cell in proliferation, migration and inhibited apoptosis in vitro, while overexpression of endothelial-derived vWF inhibited the proliferation, migration and induced apoptosis of lung cancer cells. The results of further experiments indicated that the vWF secreted by endothelial cells could affect lung cancer cell migration and apoptosis via its binding to integrin αvβ3 on the surface of lung cancer cells. Furthermore, a novel finding was the fact that endothelial-derived vWF inhibited lung cancer cell apoptosis by phosphorylating ERK1/2. At the same time, we established experimental lung metastasis model and xenograft model in normal mice and vWF−/− mice, and found that knockout of vWF in mice significantly promoted lung cancer growth and metastasis. In conclusion, our research found that endothelial-derived vWF could directly combine to αvβ3 on the exterior of A549 and 95D, thereby mediating lung cancer proliferation, migration and apoptosis and inhibiting the development of lung cancer.

A Small Molecule Targeting the Intracellular Tyrosine Kinase Domain of ROR1 (KAN0441571C) Induced Significant Apoptosis of Non-Small Cell Lung Cancer (NSCLC) Cells.

The ROR1 receptor tyrosine kinase is expressed in embryonic tissues but is absent in normal adult tissues. ROR1 is of importance in oncogenesis and is overexpressed in several cancers, such as NSCLC. In this study, we evaluated ROR1 expression in NSCLC patients (N = 287) and the cytotoxic effects of a small molecule ROR1 inhibitor (KAN0441571C) in NSCLC cell lines. ROR1 expression in tumor cells was more frequent in non-squamous (87%) than in squamous (57%) carcinomas patients, while 21% of neuroendocrine tumors expressed ROR1 (p = 0.0001). A significantly higher proportion of p53 negative patients in the ROR1+ group than in the p53 positive non-squamous NSCLC patients (p = 0.03) was noted. KAN0441571C dephosphorylated ROR1 and induced apoptosis (Annexin V/PI) in a time- and dose-dependent manner in five ROR1+ NSCLC cell lines and was superior compared to erlotinib (EGFR inhibitor). Apoptosis was confirmed by the downregulation of MCL-1 and BCL-2, as well as PARP and caspase 3 cleavage. The non-canonical Wnt pathway was involved. The combination of KAN0441571C and erlotinib showed a synergistic apoptotic effect. KAN0441571C also inhibited proliferative (cell cycle analyses, colony formation assay) and migratory (scratch wound healing assay) functions. Targeting NSCLC cells by a combination of ROR1 and EGFR inhibitors may represent a novel promising approach for the treatment of NSCLC patients.

Potent saccharinate-containing palladium(II) complexes for sensitization to cancer therapy

Palladium(II) (PdII) complexes are among the most promising anticancer compounds. Both 2`-benzoylpyridine thiosemicarbazone (BpT) and saccharinate (Sac) are efficient metal chelators with potent anticancer activity. To explore a more effective new anticancer drug, we synthesized a series of Sac and BpT-containing PdII complexes coordinated with thiosemicarbazone (TSC)-derived ligands, and characterized them through nuclear magnetic resonance (NMR), Fourier transformed infrared spectroscopy (FT-IR), elemental analysis, ultraviolet-visible spectroscopy (UV–Vis) and thermogravimetric analysis (TGA). Each target complex was composed of PdII, BpT, and one or two Sac molecules. Both the in vitro and in vivo anti-growth effects of those ligands and the obtained PdII complexes were investigated in the human lung adenocarcinoma cell lines A549 and Spc-A1. The coordination of PdII with the TSC-derivatives and Sac resulted in clearly greater anticancer activity than single ligands. These compounds were demonstrated to be safe for 293 T normal human kidney epithelial cells. The introduction of Sac into the TSC-derived PdII complex significantly enhanced anti-growth effects, and induced apoptosis of human lung cancer cells in vitro and in vivo in a dose dependent manner. Moreover, the PdII complex containing two Sac molecules showed the most promising therapeutic effects, thereby confirming that Sac increases the cancer therapeutic efficacy of PdII complexes and providing a new strategy for exploring anticancer drugs for potential clinical treatment.

MiR-183-5p regulates ECM and EMT to promote non-small cell lung cancer progression by targeting LOXL4.

Non-small cell lung cancer (NSCLC) progression is mediated by changes in gene expression induced by microRNAs. However, the underlying mechanisms remain to be elucidated. In this study, we investigated the roles of miR-183-5p and its target gene in lung cancer development. Relative levels of miR-183-5p and lysyl oxidase-like 4 (LOXL4) expression in lung cancer cells or tissues were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence or Western blotting as appropriate. The binding of miR-183-5p to LOXL4 sequences was verified by a dual luciferase reporter assay, and cell proliferation was assessed by Cell Counting Kit-8 (CCK-8) and Edu staining. The cell cycle stage and apoptosis were detected by flow cytometry, and Transwell assays were performed to evaluate cell migration and invasion capabilities. The tumorigenic capability of cancer cells was analyzed using a cancer cell line-based xenograft nude mouse model. miR-183-5p expression was decreased in the lung cancer tissues and cell lines and was negatively correlated with elevated LOXL4 expression. Treatment with miR-183-5p mimics suppressed LOXL4 expression, while treatment with an miR-183-5p inhibitor promoted LOXL4 expression in A549 cells. miR-183-5p was found to directly bind to the 3' UTR of the LOXL4 gene in A549 cells. Overexpression of LOXL4 enhanced cell proliferation, cell cycle progression, migration, and invasion, but repressed their apoptosis, and activated extracellular matrix (ECM) and the epithelial mesenchymal transition (EMT) process in A549 cells, while LOXL4 knockdown produced the opposite effects. Treatment with an miR-183-5P inhibitor promoted the proliferation, cell cycle progression, migration, and invasion of A549 cells but suppressed their apoptosis, and activated the ECM and EMT process, while all these effects were abrogated by LOXL4 knockdown. The tumorigenic capability of A540 cells in nude mice was greatly impaired by treatment with miR-183-5p mimics. miR-183-5p repressed the proliferation, migration, invasion, ECM formation, and EMT processes, and promoted the apoptosis of lung cancer cells by targeting LOXL4 expression.

MicroRNA-125a-5p as a Tumor Suppressor in Non-Small Cell Lung Cancer (NSCLC): Inhibition of Proliferation and Induction of Apoptosis via P13K/AKT/MMP Signaling Pathway

To investigate the effects of micro ribonucleic acid (miR)-125a-5p on the proliferation and apoptosis of non-small cell lung cancer (NSCLC) cells and its possible mechanism. With NSCLC A549 cells as the experimental research objects, transfection reagent was employed to transfect miR-125a-5p NC group, miR-125a-5p mimic group and miR-125a-5p siRNA group into A549 cells. qRT-PCR and cloning assays were conducted to detect the level of miR125a-5p in A549 cells and the effect of miR125a-5p on the proliferation of A549 cells. The effect of miR-125a-5p on apoptosis of A549 cells was detected via FCM. Additionally, the effects of miR-125a-5p on the mRNA and protein expressions of PI3K and AKT and the expressions of MMP-2 and MMP-9 in A549 cells were determined through qRT-PCR, Western blotting and immunohistochemistry, respectively. Compared with those in miR-125a-5p NC group, the proliferation ability of A549 cells was improved, their apoptosis rate was significantly decreased, and the mRNA and protein levels of PI3K and AKT and the levels of MMP-2 and MMP-9 in A549 cells were increased in miR-125a-5p siRNA group, whereas they showed totally opposite tendencies in miR-125a-5p mimic group. miR-125a-5p overexpression can hinder A549 cell growth, boost apoptosis, and reduce MMP-2 and MMP-9 levels via the PI3K/AKT/MMP pathway.

Organosulfur Compound Identified from Striga angustifolia (D. Don) C.J. Saldanha Inhibits Lung Cancer Growth and Induces Apoptosis via p53/mTOR Signaling Pathway.

The Striga angustifolia (D. Don) C.J. Saldanha was used as an Ayurvedic and homeopathic medicine for cancer by the tribal peoples of the Maruthamalai Hills, Coimbatore, India. Hence, the traditional use that has been proven to be effective lacks convincing scientific references. This present study was conducted to investigate the presence of potentially bioactive compounds from S. angustifolia and provides a scientific basis for the ethnobotanical utility. The organosulfur compound 5,5'-dithiobis(1-phenyl-1H-tetrazole) (COMP1) was isolated from S. angustifolia extracts, and the structures of COMP1 were elucidated and characterized by using 13C and 1H nuclear magnetic resonance (NMR) and single crystal X-ray powder diffraction (XRD). Our findings showed that COMP1 significantly reduced cell proliferation of breast and lung cancer cells, but not that of non-malignant epithelial cells. Further analysis revealed that COMP1 promoted cell cycle arrest and apoptosis of lung cancer cells. Mechanistically, COMP1 facilitates p53 activity and inhibits mammalian target of rapamycin (mTOR) signaling, thereby inducing cell cycle arrest and apoptosis of lung cancer cells by inhibiting cell growth. Our findings suggest that COMP1 may serve as a potential drug for lung cancer through the regulation of p53/mTOR pathways.

SODD Promotes Lung Cancer Tumorigenesis by Activating the PDK1/AKT and RAF/MEK/ERK Signaling.

The Bcl2-associated athanogene4 (BAG4/SODD) protein could be identified as a tumor marker for several malignancies and plays a major role in the occurrence, development, and drug resistance of tumors. However, the role of Silencer of death domains (SODD) in lung carcinogenesis is still elusive. To illuminate the effect of SODD on the proliferation, migration, invasion, and apoptosis of lung cancer cells and tumor growth in vivo and explore the corresponding mechanism. The expression of SODD in tumor and normal tissues was determined and compared via western blot. SODD gene knockout lung cancer cells (H1299 cells) were established through a CRISPR/Cas9 gene deleting system, and a transient SODD overexpression of H1299 cells was also constructed. Then, cell proliferation and invasion were assessed through colony formation and cell counting kit-8 assays, transwell migration assays, and wound healing assays. Cell drug sensitivity is also analyzed by Cell Counting Kit-8 assay. The flow cytometer was used to perform cell circle and apoptosis analysis. The interaction of SODD and RAF-1 was confirmed by co-immunoprecipitation, and the phosphorylated level of Phosphatidylinositol 3-kinase (PI3K), Serine/threonine-protein kinase (AKT), Rapidly accelerated fibrosarcoma (RAF)-1,and extracellular signal regulated kinase (ERK) in cells was examined by western blot to evaluate the activation of PI3K/PDK1/AKT and RAF/MEK/ERK pathways. In vivo, Xenograft tumor assay of SODD knockout H1299 cells was used to evaluate further the role of SODD on the proliferation of H1299 cells. SODD binds to RAF-1 and is over-expressed in lung tissues, and promotes the proliferation, migration, invasion, and drug sensitivity of H1299 cells. The reduced cells in the S phase and increased cells arrested in the G2/M phase were found in SODD knockout H1299 cells, and more cells got apoptosis. The expression of 3-phosphoinositide-dependent protein kinase 1(PDK1) protein in SODD knockout H1299 cells decreases distinctively, and the phosphorylated level of AKT, RAF-1, and ERK-1 kinase in SODD knockout H1299 cells is also less than that in normal H1299 cells. In contrast, SODD overexpression significantly increases the phosphorylation of AKT. In vivo, SODD promotes the tumorigenicity of H1299 cells in nude mice. SODD is overexpressed in lung tissues and plays a considerable role in the development and progression of lung cancer by regulating the PI3K/PDK1/AKT and RAF/MEK/ERK pathways.

SETDB1-mediated CD147-K71 di-methylation promotes cell apoptosis in non-small cell lung cancer

Protein post-translational modifications (PTMs) are at the heart status of cellular signaling events and broadly involved in tumor progression. CD147 is a tumor biomarker with various PTMs, promoting tumor metastasis and metabolism reprogramming. Nevertheless, the relationship between the PTMs of CD147 and apoptosis has not been reported. In our study, we produced a specific anti-CD147-K71 di-methylation (CD147-K71me2) antibody by immunizing with a di-methylated peptide and observed that the level of CD147-K71me2 in non-small cell lung cancer (NSCLC) tissues were lower than that in NSCLC adjacent tissues. SETDB1 was identified as the methyltransferase catalyzing CD147 to generate CD147-K71me2. RNA-seq showed that FOSB was the most significant differentially expressed gene (DEG) between wild-type CD147 (CD147-WT) and K71-mutant CD147 (CD147-K71R) groups. Subsequently, we found that CD147-K71me2 promoted the expression of FOSB by enhancing the phosphorylation of p38, leading to tumor cell apoptosis. In vivo experiments showed that CD147-K71me2 significantly inhibited tumor progression by promoting cell apoptosis. Taken together, our findings indicate the inhibitory role of CD147-K71me2 in tumor progression from the perspective of post-translational modification, which is distinct from the pro-cancer function of CD147 itself, broadening our perspective on tumor-associated antigen CD147.

Changes in the Proteome Profile of A549 Cells Following Helichrysetin-Induced Apoptosis Suggest the Involvement of DNA Damage Response and Cell Cycle Arrest-Associated Proteins.

Our previous findings demonstrated that Helichrysetin possessed promising anti-cancer activity. It was able to induce apoptosis in the A549 cell line. However, its mechanism of action is unknown. The present study aimed to unravel possible underlying molecular mechanisms of helichrysetin-induced apoptosis in A549 (human lung carcinoma) cells using comparative quantitative proteomics (iTRAQ labeled), followed by an exhaustive bioinformatics analysis. Our results suggested that DNA damage response (DDR) and cell cycle arrest were responsible for lung cancer cell death with helichrysetin treatment. Among proteins that changed in abundance were Nrf2 and HMOX1. They are oxidative stress-related proteins and were increased in abundance. BRAT1 was also increased in abundance, suggesting an increase in DNA damage repair, indicating the occurrence of DNA damage due to oxidative stress. However, several essential DDR downstream proteins such as p-ATM, BRCA1, FANCD2, and Rb1 that would further increase DNA damage were found to be dramatically decreased in relative abundance. Cell cycle-related proteins, p53, p21, and cyclin D1, were increased while cyclin A, cyclin E, and cdk2 were decreased. This is predicted to facilitate S-phase arrest. Furthermore, excessive DNA damage and prolonged arrest would in turn result in the induction of mitochondrial-mediated apoptosis. Based on these observations, we postulate that the effects of helichrysetin were in part via the suppression of DNA damage response which led to DNA damage and prolonged cell cycle arrest. Subsequently, this event initiated mitochondrial-mediated apoptosis in A549 lung cancer cells.

Warfarin affects the proliferation and apoptosis of lung cancer cells by regulating the Gas6/Axl/PI3K/Akt/NF-κB pathway

Warfarin affects the proliferation and apoptosis of lung cancer cells by regulating the Gas6/Axl/PI3K/Akt/NF-κB pathway

Key Targets and Molecular Mechanisms of the Fat-soluble Components of Ginseng for Lung Cancer Treatment

Objective: To analyze the regulatory effects and key targets of the fat-soluble components of ginseng in lung cancer. Methods: Gas chromatography–mass spectrometry and the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform were used to analyze and identify the fat-soluble components of ginseng. Network pharmacology was used to analyze the therapeutic targets of the fat-soluble components of ginseng in lung cancer and screen key proteins. In vitro assays were conducted to verify the effects of the active fat-soluble components of ginseng on proliferation and apoptosis in lung cancer cells and to verify the regulation of key proteins. Results: Ten active fat-soluble components of ginseng were screened for follow-up. Network pharmacology showed 33 overlapping targets between the active fat-soluble components of ginseng and lung cancer, and functional enrichment of the targets showed involvement of response to nitrogen, hormone response, membrane raft, and positive regulation of external stimulus. Pathway enrichment analysis showed vascular endothelial growth factor (VEGF) signaling, adipocyte lipolysis regulation, chronic myelogenous leukemia, endocrine resistance, and NSCLC-related pathways. A protein-protein interaction network was constructed, and the top 10 targets were selected in accordance with their scores. Ultimately, five target genes (EGFR, KDR, MAPK3, PTPN11, and CTNNB1) were selected in combination with literature mining for subsequent experimental verification. Proliferation assays showed that the growth of lung cancer cells was significantly decreased in a concentration-dependent manner in the fat-soluble components of ginseng intervention group compared with controls. Flow cytometry showed that active fat-soluble components of ginseng promoted apoptosis in a concentration-dependent manner in lung cancer cells. Western blot and quantitative real-time PCR showed that levels of the five key proteins and mRNAs were significantly decreased in the intervention group; furthermore, histone protein and mRNA levels were significantly higher in the high-concentration intervention group compared with the low-concentration group. Conclusion: The active fat-soluble components of ginseng inhibited the growth of lung cancer cells and promoted apoptosis. The underlying regulatory mechanisms may be related to signaling pathways involving EGFR, KDR, MAPK3, PTPN11, and CTNNB1.

Formosanin C suppresses cancer cell proliferation and migration by impeding autophagy machinery.

Formosanin C (FC) is a natural compound extracted from Paris formosana Hayata with anticancer activity. FC induces both autophagy and apoptosis in human lung cancer cells. FC-induced depolarization of mitochondrial membrane potential (MMP) may trigger mitophagy. In this study, we clarified the effect of FC on autophagy, mitophagy, and the role of autophagy in FC-related cell death and motility. We found FC caused the continuous increase of LC3 II (representing autophagosomes) from 24 to 72 h without degradation after treatment of lung and colon cancer cells, indicating that FC blocks autophagic progression. In addition, we confirmed that FC also induces early stage autophagic activity. Altogether, FC is not only an inducer but also a blocker of autophagy progression. Moreover, FC increased MMP accompanied by overexpression of COX IV (mitochondria marker) and phosphorylated Parkin (p-Parkin, mitophagy marker) in lung cancer cells, but no colocalization of LC3 with COX IV or p-Parkin was detected under confocal microscopy. Moreover, FC could not block CCCP (mitophagy inducer)-induced mitophagy. These results imply that FC disrupts mitochondria dynamics in the treated cells, and the underlying mechanism deserves further exploration. Functional analysis reveals that FC suppresses cell proliferation and motility through apoptosis and EMT-related pathway, respectively. In conclusion, FC acts as an inducer as well as a blocker of autophagy that results in cancer cell apoptosis and decreased motility. Our findings shed the light on the development of combined therapy with FC and clinical anticancer drugs for cancer treatment.

Sodium selenite inhibits proliferation of lung cancer cells by inhibiting NF-κB nuclear translocation and down-regulating PDK1 expression which is a key enzyme in energy metabolism expression

As a trace element that maintains homeostasis in human body, selenium has significant anti-tumor activity. However, its exact molecular mechanism remains to be elucidated. Sodium selenite (SSe) is the most widely-distributed inorganic selenium in nature. In this study, we selected SSe as the research object to explore its anti-tumor mechanism in lung cancer. In vitro experiment showed that SSe could inhibit the activation of NF-κB signaling pathway, knowing that NF-κB is an important intracellular nuclear transcription factor that regulates the expression of pyruvate dehydrogenase kinase 1 (PDK1), a key energy metabolism switch affecting the survival status of the whole cell.At the same time, Bay11–7082(NF-κB signaling pathway inhibitors) and SSe resulted in phosphorylation of p65 and IκBα, decreased expression of PDK1 and Bcl-2,and increased expression of Bax in lung cancer cells. Our further study demonstrated that the reduction of PDK1 activity inhibited lactate secretion, reduced mitochondrial membrane potential, caused the release of Cytochrome C (Cyto C), activated mitochondrial respiration, and promoted the apoptosis of lung cancer cells. The in vivo experiment revealed that SSe inhibited the activation of NF-κB signaling pathway, decreased the expression of PDK1, and induced lung cancer cell proliferation and apoptosis. All these findings indicated that SSe promoted lung cancer cell apoptosis by inhibiting the activation of NF-κB signaling pathway, down-regulating PDK1 and activating mitochondrial apoptosis pathway.

Cancer-targeted fucoidan‑iron oxide nanoparticles for synergistic chemotherapy/chemodynamic theranostics through amplification of P-selectin and oxidative stress

A combination of chemotherapy and chemodynamic therapy (CDT) is being developed to improve the theranostic efficacy and biological safety of current therapies. However, most CDT agents are restricted due to complex issues such as multiple components, low colloidal stability, carrier-associated toxicity, insufficient reactive oxygen species generation, and poor targeting efficacy. To overcome these problems, a novel nanoplatform composed of fucoidan (Fu) and iron oxide (IO) nanoparticles (NPs) was developed to achieve chemotherapy combined with CDT synergistic treatment with a facile self-assembling manner, and the NPs were made up of Fu and IO, in which the Fu was not only used as a potential chemotherapeutic but was also designed to stabilize the IO and target P-selectin-overexpressing lung cancer cells, thereby producing oxidative stress and thus synergizing the CDT efficacy. The Fu-IO NPs exhibited a suitable diameter below 300 nm, which favored their cellular uptake by cancer cells. Microscopic and MRI data confirmed the lung cancer cellular uptake of the NPs due to active Fu targeting. Moreover, Fu-IO NPs induced efficient apoptosis of lung cancer cells, and thus offer significant anti-cancer functions by potential chemotherapeutic-CDT.