S100A4/NF-κB axis mediates the anticancer effect of epigallocatechin-3-gallate in platinum-resistant ovarian cancer.

Resistance to cisplatin (cis-dichlorodiamineplatinum, DDP) in ovarian cancer is a significant clinical challenge. Epigallocatechin-3-gallate (EGCG) has shown promise in cancer therapy. However, its effects on DDP-resistant ovarian cancer remain understudied. This study aims to assess the impact of EGCG on DDP-resistant cells and elucidate the associated molecular mechanisms. DDP-resistant cell lines were utilized for biological characterization. EGCG effectively inhibited proliferation, mobility, and induced apoptosis in OC/DDP cells. It downregulated the expression of S100A4 and NF-κB while upregulating p53 expression. These effects were reversed upon overexpression of S100A4 or NF-κB. In vivo experiments confirmed tumor inhibition and KI67 inhibition by EGCG. Moreover, EGCG downregulated the expression of S100A4 and NF-κB while upregulating p53 in xenograft mice compared to those without EGCG treatment. This study suggests that EGCG suppresses cancer progression through the S100A4/NF-κB signaling pathway, involving interaction with p53. EGCG holds potential as an anticancer candidate for OC/DDP.

Serum cytokines and neutrophil-to-lymphocyte ratio as predictive biomarkers of benefit from PD-1 inhibitors in gastric cancer.

Background: Immunotherapy is significantly revolutionizing cancer treatment and demonstrating promising efficacy in gastric cancer (GC) patients. However, only a subset of patients could derive benefits from targeted monoclonal antibody therapy against programmed death receptor 1 (PD-1). This study aims to identify suitable serum cytokines and blood cell ratios as predictive biomarkers to aid in the selection of GC patients likely to benefit from PD-1 inhibitors. Materials and methods: This retrospective study included 41 GC patients who received PD-1 inhibitors combined with chemotherapy, 36 GC patients treated solely with chemotherapy, and 33 healthy controls. The study assessed the levels of seven cytokines: interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-17A, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and various inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR), total lymphocyte count (TLC), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR). Measurements were obtained using the inpatient system. Univariate and multivariate Cox regression analyses were performed to evaluate the predictive significance of these hematologic parameters for clinical outcomes. Results: Levels of IL-6, IL-10, TNF-α, NLR, and PLR were significantly elevated in GC patients compared to healthy controls, while TLC and LMR were higher in the control group. Among the 41 patients receiving PD-1 inhibitors and chemotherapy, baseline IL-2 was associated with OS and PFS. Additionally, IL-6 and IL-17A correlated with OS, while NLR was linked to PFS (all P<0.05). These factors were identified as independent prognostic indicators in both univariate and multivariate analyses. Furthermore, almost all cytokine levels increased following the initiation of PD-1 inhibitor treatment. Conclusions: The introduction of PD-1 inhibitors alongside chemotherapy in GC impacts serum cytokine levels. IL-2, IL-6, IL-17A, and NLR exhibit potential as reliable circulating predictive biomarkers for identifying patients who may benefit from PD-1 inhibitors combined with chemotherapy.

Organic Small Molecule Contrast Agent for Targeted Photoacoustic Imaging of Patient-Derived Brain Tumors.

Traditional glioblastoma (GBM) cell lines do not maintain the heterogeneity of the original tumor, cell interactions, and therapy response, thus limiting their investigation in GBM theranostics. Herein, a kind of GBM tumor-targeting nanoparticles (NPs) TCFNP@iRGD are designed and constructed, which are generated by photoacoustic (PA) contrast agent 2-(3-cyano-4,5,5-trimethylfuran-2(5H)-ylidene) malononitrile (TCF)-OH through facile nanoprecipitation and decorated with an active targeting ligand iRGD. Their potential in GBM detection via PA imaging on glioma patient-derived cells intracranial xenograft models is evaluated for the first time. Excellent tumor-specific PA mapping performance of GBM is realized by TCFNP@iRGD, demonstrating its promising potential in the clinical diagnosis of GBM.

Degradable Magnetic Nanoplatform with Hydroxide Ions Triggered Photoacoustic, MR Imaging, and Photothermal Conversion for Precise Cancer Theranostic.

Theranostic agents based on inorganic nanomaterials are still suffered from the nonbiodegradable substances with long-term retention in body and unavoidable biological toxicity, as well as nonspecificity biodistribution with potential damage toward normal tissues. Here, we develop magnetic ions (FeIII, FeII, GdIII, MnII, and MnIII) coordinated nanoplatform (MICN) with framework structure and modify them with PEG (MICN-PEG). Notably, MICN-PEG demonstrates hydroxide ions (OH-) triggered the structure collapse along with responsive near-infrared photoacoustic (PA) signal, magnetic resonance imaging (MRI), and photothermal therapy (PTT) performances. Thereby, MICN-PEG is able to remain stable in tumors and exert excellent PA/MRI and PTT effects for multimodal imaging-guided cancer treatment. In contrast, MICN-PEG is gradually collapsed in normal tissues, resulting in the significant improvement of imaging accuracy and treatment specificity. MICN-PEG is gradually cleared after administration, minimizing concerns about the long-term toxicity.

TRPM2-AS promotes the malignancy of osteosarcoma cells by targeting miR-15b-5p/PPM1D axis.

Osteosarcoma (OS) is a malignant tumor with a low survival rate and a high incidence rate worldwide. Although research has reported the involvement of long non-coding RNAs (lncRNAs) in the pathogenesis of OS cells, the role of TRPM2-AS, miR-15b-5p, and PPM1D in OS progression remains unclear. This study aimed to examine the interaction of the TRPM2-AS/miR-15b-5p/PPM1D axis in OS cells to gain new insights into the molecular mechanism and pathogenesis of OS. After performing in vitro functional assays, we discovered that TRPM2-AS was overexpressed in OS cells. TRPM2-AS silencing impaired OS cell viability, proliferation, and migration, while it induced apoptosis in OS cells in vitro. Our experimental analysis also revealed that PPM1D is a direct target of miR-15b-5p. TRPM2-AS silencing was found to reverse the tumorigenic effect of the miR-15b-5p inhibitor, while the miR-15b-5p inhibitor restored the inhibition of OS caused by silencing PPM1D. Moreover, our findings revealed that miR-15b-5p exerted its tumor-suppressive role by directly targeting PPM1D. In conclusion, this study suggests that TRPM2-AS could promote OS cell malignancy by sponging miR-15b-5p/PPM1D axis.

LncRNA HCP5 Induces Gastric Cancer Cell Proliferation, Invasion, and EMT Processes Through the miR-186-5p/WNT5A Axis Under Hypoxia.

OBJECTIVE: To experimentally determine the involvement and mechanism of long non-coding RNA (lncRNA) HCP5 in the development of gastric cancer (GC). METHODS: Detection of HCP5, miR-186-5p, and WNT5A expression in clinical GC tissues and adjacent healthy tissues was performed, followed by Pearson correlation analysis. BGC-823 and AGS cells, with interferences of HCP5, miR-186-5p, and WNT5A, were cultured under hypoxia. MTT, colony formation assay, Caspase-3 activity assay, and transwell assay were applied for the determination of cell proliferation, viability, apoptosis, and invasion, respectively. Expressions of WNT5A and protein markers of epithelial-mesenchymal transition (EMT) in cells were detected by western blotting. And the binding of HCP5 and WNT5A to miR-186-5p was validated using dual-luciferase reporter assay. RESULTS: In GC tissues, an increase in HCP5 and WNT5A expressions and a reduction in miR-186-5p expression were found, and the negative correlation between miR-186-5p and HCP5/WNT5A was proven. Subsequently, under hypoxia, an increase in HCP5 and WNT5A expressions and a decrease in miR-186-5p expression in GC cells were confirmed. In addition, in GC cells under hypoxia, the inhibition of HCP5 suppressed cell biological activity and EMT, while the inhibition of miR-186-5p or the overexpression of WNT5A led to the opposite changes. CONCLUSION: An upregulation of WNT5A expression by HCP5 competitively binding to miR-186-5p promotes GC cell development.

LncRNA CTBP1-AS2 Facilitates Gastric Cancer Progression via Regulating the miR-139-3p/MMP11 Axis.

BACKGROUND: This study aimed at probing into the effect of long non-coding RNA (lncRNA) C-terminal binding protein 1 antisense RNA 2 (CTBP1-AS2) on gastric cancer (GC) cell proliferation and apoptosis, and its regulatory function on miR-139-3p and MMP11. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to examine the expressions of CTBP1-AS2, miR-139-3p and MMP11 mRNA in GC cell lines and clinical specimens. Cell counting kit-8 (CCK-8) assay, flow cytometry and EdU assay were conducted to examine the effects of CTBP1-AS2 and miR-139-3p on GC cell proliferation and apoptosis. Western blot was applied for detecting the expressions of Bax, Bcl-2 and MMP11. A lung metastasis mouse model was used to evaluate metastasis of GC cells in vivo. Bioinformatics, dual-luciferase report assay, RIP and RNA pull-down assays were utilized to validate the targeted relationship between CTBP1-AS2 and miR-139-3p as well as the targeting relationship between miR-139-3p and MMP11. RESULTS: CTBP1-AS2 was highly expressed in GC, and its high expression was strongly associated with increased TNM stage, increased tumor size and low degree of differentiation of the tumor tissues. Meanwhile, CTBP1-AS2 promoted GC cell proliferation, metastasis and suppressed apoptosis, while miR-139-3p could weaken these effects. In addition, CTBP1-AS2 was identified as a molecular sponge for miR-139-3p, and MMP11 was verified as a target gene of CTBP1-AS2. CTBP1-AS2 could increase the expression of MMP11 via repressing miR-139-3p. CONCLUSION: CTBP1-AS2 promotes GC cells and inhibits apoptosis by regulating the miR-139-3p/MMP11 molecular axis.

Long Non-Coding RNA NEAT1 Serves as Sponge for miR-365a-3p to Promote Gastric Cancer Progression via Regulating ABCC4.

INTRODUCTION: Long non-coding RNA (lncRNA) was reported to be a crucial regulator in cancer. In this work, our purpose is to explore the biological roles of nuclear paraspeckle assembly transcript 1 (NEAT1) in gastric cancer (GC). METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect NEAT1 expression in GC cells and normal cells. GC cell behaviors after NEAT1 overexpression or downregulation were analyzed by Cell Counting Kit-8 assay, colony formation assay, wound-healing assay, and flow cytometry assay. Bioinformatic tools were used to analyze the significance of NEAT1 in GC. The involvement of microRNA-365a-3p (miR-365a-3p) and ATP-binding cassette subfamily C member 4 (ABCC4) in the biological roles of NEAT1 in GC progression was validated by luciferase activity reporter assay and rescue experiments. RESULTS: We found NEAT1 increased expression in both GC tissues and cells and correlated with poorer overall survival of cancer patients. We found NEAT1 overexpression promotes, while its knockdown inhibits GC cell proliferation, colony formation, invasion, and cell cycle progression in vitro. Mechanism analyses showed that NEAT1 serves as a ceRNA to upregulate ABCC4 expression via sponging miR-365a-3p. CONCLUSION: In this study, we revealed a NEAT1/miR-365a-3p/ABCC4 triplet in GC progression, which may provide novel targeted therapy markers for GC.

Noninvasive temperature monitoring for dual-modal tumor therapy based on lanthanide-doped up-conversion nanocomposites.

Accurate treatment of photothermal therapy (PTT) is crucial to avoid the unnecessary injury of normal cells and tissues. Therefore the real-time temperature monitoring in the PTT process has drawn more and more attention in recent years. Herein, we designed and prepared one kind of lanthanide (Ln3+)-doped up-conversion nanocomposites with multi-functions, which can not only provide temperature feedback in PTT process, but also play the photodynamic therapy (PDT) function for the synergistic effect of tumor therapy. Based on NaYF4:Yb, Er up-conversion nanoparticles (UCNPs), mesoporous SiO2 was modified on the surface combined with photosensitizer Chlorin e6 (Ce6) molecules, which could be excited by red emission of Er3+ under the 980 nm laser. Cit-CuS NPs were further linked on the surface of the composite served as photothermal conversion agent, therefore, the temperature of the PTT site can be monitored by recording the ratio of I525/I545 of green emissions, especially within the physiological range. Based on the guidance obtained from spectral experiments, we further investigated the dual-modal therapy effect both in vitro and in vivo, respectively, and acquired decent results.

The Effect of Photothermal Therapy on Osteosarcoma With Polyacrylic Acid-Coated Gold Nanorods.

BACKGROUND: Polyacrylic acid (PAA)-coated gold nanorods (GNRs) were prepared in this research, and then the structure, stability, temperature increment efficiency, and biocompatibility of GNRs@PAA were detected. METHODS: It was demonstrated that GNRs@PAA coupled with an 808 nm laser had superior efficiency of hyperthermia therapy for MG63 human osteosarcoma cell. RESULTS: The mechanism of photothermal therapy of GNRs@PAA was explored, and it was proved that damaged cell membrane and DNA integration caused cell apoptosis and death, and the cell apoptosis rate had been obviously promoted by in vitro photothermal therapy which exhibited time-dose dependence. CONCLUSION: The results demonstrated that the GNRs@PAA could be a promising candidate for phototherapeutic applications in human osteosarcoma.

Design of efficient bifunctional catalysts for direct conversion of syngas into lower olefins via methanol/dimethyl ether intermediates.

The direct conversion of syngas into lower olefins is a highly attractive route for the synthesis of lower olefins. The selectivity of lower olefins via the conventional Fischer-Tropsch (FT) synthesis is restricted to ∼60% with high CH4 selectivity due to the limitation by the Anderson-Schulz-Flory (ASF) distribution. Here, we report the design of bifunctional catalysts for the direct conversion of syngas into lower olefins with selectivity significantly breaking the ASF distribution. The selectivity of C2-C4 olefins reached 87% at a CO conversion of 10% and was sustained at 77% by increasing CO conversion to 29% over a bifunctional catalyst composed of Zn-doped ZrO2 nanoparticles and zeolite SSZ-13 nanocrystals. The selectivity of CH4 was lower than 3% at the same time. It is demonstrated that the molar ratio of Zn/Zr, the density of Brønsted acid sites of SSZ-13 and the proximity of the two components play crucial roles in determining CO conversion and lower-olefin selectivity. Our kinetic studies indicate that methanol and dimethyl ether (DME) are key reaction intermediates, and the conversion of syngas to methanol/DME is the rate-determining step over the bifunctional catalyst. Formate and methoxide species have been observed on Zn-doped ZrO2 surfaces during the activation of CO in H2, and the formed methanol/DME are transformed into lower olefins in SSZ-13.

Three-Dimensional Inverse Opal Photonic Crystal Substrates toward Efficient Capture of Circulating Tumor Cells.

Artificial fractal structures have attracted considerable scientific interest in circulating tumor cells (CTCs) detection and capture, which plays a pivotal role in the diagnosis and prognosis of cancer. Herein, we designed a bionic TiO2 inverse opal photonic crystal (IOPC) structure for highly efficient immunocapture of CTCs by combination of a magnetic Fe3O4@C6@silane nanoparticles with anti-EpCAM (antiepithelial cell adhesion molecule) and microchannel structure. Porous structure and dimension of IOPC TiO2 can be precisely controlled for mimicking cellular components, and anti-EpCAM antibody was further modified on IOPC interface by conjugating with polydopamine (PDA). The improvement of CTCs capture efficiency reaches a surprising factor of 20 for the IOPC interface compared to that on flat glass, suggesting that the IOPCs are responsible for the dramatic enhancement of the capture efficiency of MCF-7 cells. IOPC substrate with pore size of 415 nm leads to the optimal CTCs capture efficiency of 92% with 1 mL/h. Besides the cell affinity, IOPCs also have the advantage of light scattering property which can enhance the excitation and emission light of fluorescence labels, facilitating the real-time monitoring of CTCs capture. The IOPC-based platform demonstrates excellent performance in CTCs capture, which will take an important step toward specific recognition of disease-related rare cells.

The Synergistic Effect of Microwave Radiation and Hypergravity on Rats and the Intervention Effect of Rana Sylvatica Le Conte Oil.

AIM: The phenomena of hypergravity and microwave radiation are widespread, which cause more and more concern for the hazards to human health. The aim of this study was to investigate the synergistic effect of microwave radiation and hypergravity on rats and observe the protective effect of Rana sylvatica Le conte oil. METHODS: Rats were exposed to microwave radiation and hypergravity, and the rat weight, the climbing pole height, serum enzyme activities, blood urea nitrogen concentration, and total antioxidant capacity were detected. RESULTS: The climbing pole height, the activities of choline acetyl transferase and cholinesterase, and the total antioxidant capacity decreased, whereas the activities of alanine aminotransferase, aspartate aminotransferase, areatine kinase, isocitric dehydrogenase, hydroxybutyrate dehydrogenase, and the blood urea nitrogen concentration increased in the hypergravity irradiation group as compared with the others. CONCLUSION: These results imply that the motion and nervous system of rats might be affected critically by the synergistic effect of microwave radiation and hypergravity, and it causes damage to most rat organs, such as the bone, skeletal muscle, liver, heart, and kidney, and the antioxidant effect is also damaged, while the injury resulted from it could be protected by Rana sylvatica Le conte oil.

High purity microfluidic sorting and in situ inactivation of circulating tumor cells based on multifunctional magnetic composites.

Detection and isolation of circulating tumor cells (CTCs) play a pivotal role in the diagnosis and prognosis of cancer, while the high capture efficiency and purity of CTCs are difficult to achieve simultaneously among the various isolation methods. In this work, we designed an inverted microchip integrating silicon nanowires (SiNWs) and multifunctional magnetic nanocomposites (Fe3O4@C6/Ce6@silane, Coumarin 6 (C6), Chlorin e6 (Ce6)) for enhanced capture efficiency and purity of CTCs. The Fe3O4@C6/Ce6@silane conjugated with antibody can label the CTCs and pull them to the upside SiNWs capture surface by the upward magnetic field with high purity. This inverted structure was also featured with real-time detection and photodynamic therapy (PDT) of CTCs with the confocal laser scanning microscope (CLSM). The results indicate the important role of the composites labels and the magnetic field, which greatly improves the capture purity of the CTCs to 90%. Meanwhile, capture efficiency of CTCs achieve to 90.3% in culture medium and 82% in blood with 2 mL/h flow rate, respectively. Based on the structure of the device and composites, the captured CTCs could be directly inactivated by the in situ photodynamic therapy in the capture process which holds positive impact to block cancer spread.

Characterization of multidrug­resistant osteosarcoma sublines and the molecular mechanisms of resistance.

Multidrug resistance (MDR) is a challenge for the treatment of cancer and the underlying molecular mechanisms remain elusive. The current study exposed MG63 osteosarcoma cells to increasing concentrations of vincristine (VCR) to establish four VCR­resistant MG63/VCR cell sublines (MG63/VCR1, 2, 3 and 4). The drug resistance indices (RI) of these sublines was detected with the CCK­8 assay and determined to be163, 476, 1,247, and 2,707­fold higher than that of parental cells, respectively. These sublines also exhibited cross­resistance to doxorubicin, paclitaxel and pirarubicin. With increased RI, the proliferative capacity of these sublines was gradually reduced and cell morphology was also altered, characterized by increased formation of pseudopodia and long cytoplasmic processes at opposite poles. However, the migration capacity and expression of certain drug resistance­associated genes were not in accordance with the increased RI; multidrug resistance protein 1 (MDR1) expression was significantly increased in these sublines compared with parental cells. However, in the highly resistant MG63/VCR3 and MG63/VCR4 cells, MDR­associated protein 1, topoisomerase II and LIM domain kinase 1 levels were significantly reduced compared with the moderately resistant MG63/VCR2 cells. Expression of glutathione S­transferase­π mRNA was determined using reverse transcription­quantitative polymerase chain reaction and determined that it was not changed between MG63 and MG63/VCR cells. The data of the present study demonstrated that the molecular alterations of drug resistance may change with the degree of drug resistance. Taking cell morphology into consideration, the intratumor clonal and phenotypic heterogeneity may be responsible for drug resistance. These MG63/VCR sublines may be a valuable tool to assess drug resistance and the underlying mechanisms, and to identify novel drug resistance­associated genes or strategies to overcome MDR in human osteosarcoma.

Targeting CD133high Colorectal Cancer Cells In Vitro and In Vivo With an Asymmetric Bispecific Antibody.

A critical obstacle in advanced colorectal cancer (CRC) treatment is the insufficient improvement on survival of conventional chemotherapy. Cancer stem cells are reported to be one of the crucial explanations. CD133 has been identified as a surface marker of CRC stem cells. Bispecific antibodies (BiAbs) targeting tumor-specific antigens are promising therapeutics for malignant diseases, yet that targeting CD133 produced by genetic engineering has not been published. In the current research, CD133 expression in primary CRC was detected by immunohistochemistry, and an asymmetric BiAb consisting of monomer of chimeric AC133 (mouse anti-human CD133 monoclonal antibody) and single chain of humanized OKT3 was developed to eradicate CD133-expressing tumor cells by arming activated T cells in vitro and in vivo. In immunohistochemical examination, CD133 overexpression (>50% of stained cells) frequency was significantly correlated with lymphatic invasion and clinical stage. The new molecular revealed dual-antigen-binding specificity to CD133 and CD3, its distinct structure not only facilitated the purification procedure but also conferred the antibody to ensure a longer and stronger cytotoxic activity. By arming activated T cells, the new antibody displayed impressive cytotoxicity toward CD133(high) but not CD133(low) CRC cells in vitro, produced amounts of cytokines (interferon-γ and granulocyte-macrophage colony-stimulating factor), and could inhibit tumor growth and retard tumor development in nonobese diabetic-severe combined immunodeficient mice without apparent toxicity. Taken together, the new BiAb possesses prosperities that support that the molecule has the potential of being a promising candidate of new therapeutics for CRC therapy.

Low expression of RSK4 predicts poor prognosis in patients with colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of cancer-related death all over the world. Ribosomal s6 kinase4 (RSK4), an X-linked gene, firstly was found as to be a potential tumor suppressive gene in a variety of cancers and is widely participated in signaling pathway. However its role in CRC is unclear. This study is to explore the correlation between the protein expression of RSK4 and clinical pathologic characteristics in colorectal tumors, which might serve as a prognostic determinant of colorectal cancers. METHODS: Biopsies of 103 colorectal cancer and 46 matched adjacent noncancerous tissues were collected for analysis of RSK4 protein by immunohistochemistry. The correlation between RSK4 protein expression and the clinical pathological features of colorectal cancers were evaluated by Chi-square test and Fisher's exact test. The survival rates were analyzed by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was analyzed by the Cox proportional hazard models. RESULTS: RSK4 was conversely correlated with some pathological classifications (P<0.05 for N, G and clinical staging), and there were no statistically significant differences in age, CEA expression in blood, CA199 and tumors t-staging (x(2) test, P>0.05 for all categories) respectively. Furthermore, patients with high protein level of RSK4 showed prolonged overall survivals (P<0.05). Moreover, multivariate analysis showed that low expression level of RSK is an independent risk factor for high mortality in colorectal cancer. CONCLUSIONS: Low RSK4 expression is correlated with advanced clinical pathologic classifications and is a poor overall survival in colorectal cancer patients. These findings suggest that RSK4 may serve as a useful marker in prognostic evaluation for patients with colorectal cancer.

Regulation of cofilin activity by CaMKII and calcineurin.

Cofilin promotes actin filament turnover by severing and depolymerizing actin filaments. Cofilin is inactivated by phosphorylation on Ser-3 by LIM-kinase1 (LIMK1) and is activated when protein phosphatase Slingshot-1L (SSH1L) dephosphorylates this residue. The authors have shown that Ca-induced cofilin dephosphorylation is mediated by calcineurin (Cn)-dependent activation of SSH1L. In this study, Ca/calmodulin-dependent protein kinase II (CaMKII) is shown to negatively regulate SSH1L activity and bind to SSH1L in a complex with 14-3-3. Phosphorylation of LIMK1 by CaMKII and its subsequent activation regulates the subcellular localization of SSH1L. Based on these findings, the authors suggest that CaMKII and Cn provide a switch-like mechanism that controls Ca-dependent LIMK1, SSH1L and cofilin activation, and subsequently actin cytoskeletal reorganization.

Overexpression of LIMK1 promotes migration ability of multidrug-resistant osteosarcoma cells.

Multidrug resistance (MDR) to chemotherapy is a major obstacle in the treatment of cancer and the resistance process is multifactorial. Studies on multidrug resistance mechanisms relied on the availability of cancer multidrug resistance cell lines that have been established. In this study we successfully established a multidrug resistance cell line MG63/VCR derived from human osteosarcoma cell line MG63 based on the induction by vincristine. MG63/VCR cells exhibited high resistance to vincristine and other anticancer drugs, accompanied by upregulated expression of MDR-associated genes MDR1, MRP1, and Bcl-2. Notably, we found that MG63/VCR cells exhibited higher migration ability compared to parental MG63 cells. Moreover, we demonstrated that LIMK1, a key regulator of actin cytoskeleton, was overexpressed at both mRNA and protein levels in MG63/VCR cells and the higher LIMK1 protein level was correlated with higher level of phosphorylated cofilin. In addition, knockdown of LIMK1 abolished the higher migration ability of MG63/ VCR cells. These results suggest that LIMK1 overexpression contributes to the invasion and metastasis of drug-resistant osteosarcoma and reveal LIMK as a novel therapeutic target for drug resistant osteosarcoma.