The immunosuppressive landscape in tumor microenvironment.

Recent advances in cancer immunotherapy, especially immune checkpoint inhibitors (ICIs), have revolutionized the clinical outcome of many cancer patients. Despite the fact that impressive progress has been made in recent decades, the response rate remains unsatisfactory, and many patients do not benefit from ICIs. Herein, we summarized advanced studies and the latest insights on immune inhibitory factors in the tumor microenvironment. Our in-depth discussion and updated landscape of tumor immunosuppressive microenvironment may provide new strategies for reversing tumor immune evasion, enhancing the efficacy of ICIs therapy, and ultimately achieving a better clinical outcome.

Tozasertib activates anti-tumor immunity through decreasing regulatory T cells in melanoma.

Although immune checkpoint therapy has significantly improved the prognosis of patients with melanoma, urgent attention still needs to be paid to the low patient response rates and the challenges of precisely identifying patients before treatment. Therefore, it is crucial to investigate novel immunosuppressive mechanisms and targets in the tumor microenvironment in order to reverse tumor immune escape. In this study, we found that the cell cycle checkpoint Aurora kinase B (AURKB) suppressed the anti-tumor immune response, and its inhibitor, Tozasertib, effectively activated T lymphocyte cytokine release in vitro and anti-tumor immunity in vivo. Tozasertib significantly inhibited melanoma xenograft tumor growth by decreasing the number of inhibitory CD4+ Treg cells in the tumors, which, in turn, activated CD8+ T cells. Single-cell analysis revealed that AURKB suppressed anti-tumor immunity by increasing MIF-CD74/CXCR4 signaling between tumor cells and lymphocytes. Our study suggests that AURKB is a newly identified anti-tumor immunity suppressor, whose inhibitors may be developed as novel anti-tumor immunity drugs and may have synergistic anti-melanoma effects with immune checkpoint therapies.

Rucaparib inhibits lung adenocarcinoma cell proliferation and migration via the SHCBP1/CDK1 pathway.

Src homolog and collagen homolog binding protein 1 (SHCBP1) binds to the SH2 domain of SHC-transforming protein 1 (SHC1) and is involved in midbody organization and cytokinesis completion. SHCBP1 has been reported to be a cancer driver gene, promoting cancer progression. However, the functional role and underlying mechanism of SHCBP1 in regulating lung adenocarcinoma (LUAD) cell proliferation and migration are incompletely understood. Here, we discovered that SHCBP1 is overexpressed in LUAD tissues and is associated with a poor prognosis. SHCBP1 knockdown inhibited LUAD cell proliferation and migration by arresting the cell cycle and preventing epithelial-mesenchymal transition (EMT) via decreasing cyclin-dependent kinase 1 (CDK1) expression. Mechanistically, CDK1 overexpression reversed SHCBP1 knockdown-induced inhibition of proliferation and migration, confirming CDK1 as a key downstream target of SHCBP1. In addition, we proposed that rucaparib may be a small-molecule inhibitor of SHCBP1 and validated both in vitro and in vivo that rucaparib inhibits cell proliferation and migration via suppression of the SHCBP1/CDK1 pathway in LUAD. Our study elucidates a newly identified role of SHCBP1 in promoting cell proliferation and migration in LUAD, and suggests rucaparib as a potential inhibitor for LUAD treatment.

A celastrol-based nanodrug with reduced hepatotoxicity for primary and metastatic cancer treatment.

BACKGROUND: Cancer is the world's leading cause of death and a key hindrance to extending life expectancy. Celastrol, a bioactive compound derived from Tripterygium wilfordii, has been shown to have excellent antitumor activity, but its poor solubility and severe organ toxicity side effects have hampered its clinical application. METHODS: In this study, a self-assembled nanodrug (PLC-NP) was designed to deliver celastrol to tumor sites while efficiently reducing its side effects by conjugating celastrol with the bioactive material LMWH and P-selectin targeting peptide (PSN). Extensive in vitro and in vivo experiments were performed to investigate both therapeutic efficacy and adverse effects. Furthermore, the specific mechanism of the antitumor activity has also been explored. FINDING: The PLC-NP nanodrugs were spherical in shape, with a mean particle size of 115.83 ± 6.93 nm. PLC-NP was sufficiently stable during blood circulation, with a selective target to P-selectin-highly expressed tumor cells, followed by releasing the containing celastrol under acidic environment and high levels of esterase in tumor cells. Both in vitro and in vivo results confirmed that celastrol's antitumor and anti-metastatic abilities were not attenuated and were actually strengthened after being formed into nanodrugs. More importantly, the organ toxicities of the modified celastrol nanodrug were dramatically reduced. Mechanistic study indicated that the inactivation of PI3K/Akt/mTOR signaling pathway and ROS-mediated mitochondrial dysfunction play critical roles in celastrol-mediated autophagy and apoptosis. INTERPRETATION: Our findings could offer a potential strategy for the translation of toxic compounds into clinical therapeutic nanomedicine. FUNDING: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.

Cu2-xSe nanoparticles suppress cell proliferation and migration in hepatocellular carcinoma by impairing mitochondrial respiration.

Cu2-xSe nanoparticles (Cu2-xSe NPs) as a new therapeutic drug platform is widely used in disease treatment due to their strong near-infrared optical absorption. In recent years, with their continuous expansion of applications in different fields, their own biological effects have received increasing attention. However, little is known about the effect of Cu2-xSe NPs on cancer cell. In this research, we found that Cu2-xSe NPs inhibited proliferation of HepG2 cells (IC50: 15.91µM) and SMMC-7721 cells (IC50: 43.15µM) and they mainly induced cell cycle arrest at the G2/M phase. Moreover, Cu2-xSe NPs inhibited HepG2 and SMMC-7721 cell migration and lamellopodia formation. Further studies indicated that Cu2-xSe NPs impaired mitochondrial respiration by inhibiting electron transport chain complex activity, thus reducing adenosine triphosphate levels. The insufficient energy supply subsequently impaired actin cytoskeleton assembly, ultimately inhibiting HepG2 and SMMC-7721 cell proliferation and migration. These findings suggest that Cu2-xSe NPs may have potentially antitumor activity, which might provide new insights of NPs into specific cancer treatment.

A Dynamic Bayesian Model for Breast Cancer Survival Prediction.

OBJECTIVE: Predicting breast cancer survival and targeting patients at high-risk of mortality is of crucial importance. METHODS: We built a Bayesian Dynamic Cox (BDCox) model for predicting 5-year overall survival in breast cancer patients using data of the SEER Cancer Registry with 12,840 women. Four feature selection methods were used to identify predictors and enhance parsimony: fast backward variable selection, elastic net, Bayesian Model Average (BMA), and clinical expertise. All resulting models and a baseline full model containing all features were internally validated via bootstrapping and externally validated in the Shanghai Breast Cancer Survival Study. RESULTS: BMA outperformed other feature selection methods in both internal and external validations. The BDCox model with 12 predictors had the best performance. Several predictors showed time-varying associations with survival that are in agreement with previous studies. CONCLUSION: The model developed using BDCox outperformed other prognostic models considered in our study. The internal validation results indicate that the BDCox model is capable of achieving high prediction accuracy (C-statistic: 0.802), and the external validation results showed excellent generalizability of the BDCox model (C-statistic: 0.739). SIGNIFICANCE: We built a dynamic Bayesian model from the large population-based registry SEER for predicting 5-year breast cancer overall survival. The prediction performance of the BDCox model is significantly better than other survival models.

Effective Triple-Negative Breast Cancer Targeted Treatment Using iRGD-Modified RBC Membrane-Camouflaged Nanoparticles.

INTRODUCTION: Triple-negative breast cancer (TNBC) has the high degree of malignancy and aggressiveness. There is no targeted therapy drug. Many studies have shown that RBC membrane-coated nanoparticles achieve biological camouflage. In addition, the RGD module in the iRGD mediates the penetration of the vector across the tumor blood vessels to the tumor tissue space. Therefore, we developed iRGD-RM-(DOX/MSNs) by preparing MSNs loaded with doxorubicin as the core, and coating the surface of the MSNs with iRGD-modified RBC membranes. METHODS: iRGD-RM-(DOX/MSNs) were fabricated using physical extrusion. In addition, their physical and chemical characterization, hemolytic properties, in vivo acute toxicity and inflammatory response, in vitro and in vivo safety, and qualitative and quantitative cellular uptake by RAW 264.7 cells and MDA-MB-231 cells were evaluated and compared. Furthermore, we examined the antitumor efficacy of iRGD-RM-(DOX/MSN) nanoparticles in vitro and in vivo. RESULTS: iRGD-RM-(DOX/MSNs) have reasonable physical and chemical properties. iRGD-RM-(DOX/MSNs) escaped the phagocytosis of immune cells and achieved efficient targeting of nanoparticles at the tumor site. The nanoparticles showed excellent antitumor effects in vivo and in vitro. CONCLUSION: In this study, we successfully developed biomimetic iRGD-RM-(DOX/MSNs) that could effectively target tumors and provide a promising strategy for the effective treatment of TNBC.

Platelet Membrane-Coated and VAR2CSA Malaria Protein-Functionalized Nanoparticles for Targeted Treatment of Primary and Metastatic Cancer.

Metastasis is the main cause of death in cancer patients. The efficacy of pharmacological therapy for cancer is limited by the heterogeneous nature of cancer cells and the lack of knowledge of microenvironments in metastasis. Evidence has shown that activated platelets possess both tumor-homing and metastasis-targeting properties via intrinsic cell adhesion molecules on platelets, and malaria protein VAR2CSA is able to specifically bind to oncofetal chondroitin sulfate, which is overexpressed on cancer cells with both epithelial and mesenchymal phenotypes. Inspired by these mechanisms, we developed a recombinant VAR2CSA peptide (rVAR2)-modified activated platelet-mimicking nanoparticles (rVAR2-PM/PLGA-ss-HA) by coating the surface of disulfide-containing biodegradable PLGA conjugate nanoparticles (PLGA-ss-HA) with an activated platelet membrane. The results demonstrated that the engineered 122 nm rVAR2-PM/PLGA-ss-HA inherited the innate properties of the activated platelet membrane and achieved enhanced homing to both primary and metastatic foci. The nanoparticles were endocytosed and responded to a high intracellular concentration of reduced glutathione, resulting in nanoparticle disintegration and the release of chemotherapeutic drugs to kill tumor cells. Thus, rVAR2-decorated activated platelet-targeting nanoparticles with controlled drug release provide a promising drug delivery strategy for efficient treatment of primary and metastatic cancer.

Novel role of CAP1 in regulation RNA polymerase II-mediated transcription elongation depends on its actin-depolymerization activity in nucleoplasm.

Lung cancer is one of the most intractable diseases with high incidence and mortality worldwide. Adenylate cyclase-associated protein 1 (CAP1), a well-known actin depolymerization factor, is recently reported to be an oncogene accelerating cancer cell proliferation. However, the physiological significance of CAP1 in lung cancer is incompletely understood and the novel functions of CAP1 in transcriptional regulation remain unknown. Here we found that CAP1 was highly expressed in lung cancer tissues and cells, which was also negatively associated with prognosis in lung cancer patients. Moreover, CAP1 promoted A549 cells proliferation by promoting protein synthesis to accelerate cell cycle progression. Mechanistically, we revealed that CAP1 facilitated cyclin-dependent kinase 9 (CDK9)-mediated RNA polymerases (Pol) II-Ser2 phosphorylation and subsequent transcription elongation, and CAP1 performed its function in this progress depending on its actin-depolymerization activity in nucleoplasm. Furthermore, our in vivo findings confirmed that CAP1-promoted A549 xenograft tumor growth was associated with CDK9-mediated Pol II-Ser2 phosphorylation. Our study elucidates a novel role of CAP1 in modulating transcription by promoting polymerase II phosphorylation and suggests that CAP1 is a newly identified biomarker for lung cancer treatment and prognosis prediction.

Bioaccumulation of cadmium in different genotypes of wheat crops irrigated with different sources of water in agricultural regions.

The study was carried out to evaluate the health risks associated with accumulation of cadmium in the different genotypes of wheat, grown in agricultural regions of Punjab, Pakistan. Five genotypes irrigated with three varied water sources were selected randomly from each region. Among all sources of water, types of soil, and grain samples, the cadmium (Cd) quantities were found (2.24-2.82 mg/L, 1.75-4.16 mg/kg, 0.86-1.90, respectively), exceeding the maximum permissible limits (0.01 mg/L, 1.1 mg/kg, 0.2 mg/kg, respectively) described by FAO/WHO. The pollution load index (PLI) exhibited by all of the samples was higher than 1.00, the permissible limit; however, other factors including bioaccumulation, translocation, bio-concentration, daily intake, and enrichment values of Cd were less than 1.00. Moreover, the health risk index for cadmium in all types of wheat grain samples was less than 1.00. The study concluded that the continuous use of wastewater resources may lead to the accumulation of cadmium in the vital body organs that may cause severe health hazards.

CBX4 promotes the proliferation and metastasis via regulating BMI-1 in lung cancer.

Proliferation and metastasis are significantly malignant characteristics of human lung cancer, but the underlying molecular mechanisms are poorly understood. Chromobox 4 (CBX4), a member of the Polycomb group (PcG) family of epigenetic regulatory factors, enhances cellular proliferation and promotes cancer cell migration. However, the effect of CBX4 in the progression of lung cancer is not fully understood. We found that CBX4 is highly expressed in lung tumours compared with adjacent normal tissues. Overexpression of CBX4 significantly promotes cell proliferation and migration in human lung cancer cell lines. The knockdown of CBX4 obviously suppresses the cell growth and migration of human lung cancer cells in vitro. Also, the proliferation and metastasis in vivo are blocked by CBX4 knockdown. Furthermore, CBX4 knockdown effectively arrests cell cycle at the G0/G1 phase through suppressing the expression of CDK2 and Cyclin E and decreases the formation of filopodia through suppressing MMP2, MMP9 and CXCR4. Additionally, CBX4 promotes proliferation and metastasis via regulating the expression of BMI-1 which is a significant regulator of proliferation and migration in lung cancer cells. Taken together, these data suggest that CBX4 is not only a novel prognostic marker but also may be a potential therapeutic target in lung cancer.

[Corrigendum] Lycorine inhibits cell proliferation and migration by inhibiting ROCK1/cofilin­induced actin dynamics in HepG2 hepatoblastoma cells.

After having carefully checked the original data of Fig. 3, the authors noted that the student in their research group had inadvertently selected incorrect images for the 10 and 20 µM lycorine experiments to show the effect of lycorine on the migration of HepG2 cells during the figure compilation process. The corrected version of Fig. 3 is shown. The authors confirm that this error did not influence the statistical analysis shown for the migration of the cells, and neither were the overall results and conclusions of this article affected. The authors appreciate this opportunity to correct the scientific record, and all authors agree with this correction. Furthermore, the authors apologize for not noticing this error prior to publication, and for any inconvenience caused. [the original article was published in Oncology Reports 40: 2298­2306, 2018; DOI: 10.3892/or.2018.6609].

ROCK1 induces dopaminergic nerve cell apoptosis via the activation of Drp1-mediated aberrant mitochondrial fission in Parkinson's disease.

Dopamine deficiency is mainly caused by apoptosis of dopaminergic nerve cells in the substantia nigra of the midbrain and the striatum and is an important pathologic basis of Parkinson's disease (PD). Recent research has shown that dynamin-related protein 1 (Drp1)-mediated aberrant mitochondrial fission plays a crucial role in dopaminergic nerve cell apoptosis. However, the upstream regulatory mechanism remains unclear. Our study showed that Drp1 knockdown inhibited aberrant mitochondrial fission and apoptosis. Importantly, we found that ROCK1 was activated in an MPP+-induced PD cell model and that ROCK1 knockdown and the specific ROCK1 activation inhibitor Y-27632 blocked Drp1-mediated aberrant mitochondrial fission and apoptosis of dopaminergic nerve cells by suppressing Drp1 dephosphorylation/activation. Our in vivo study confirmed that Y-27632 significantly improved symptoms in a PD mouse model by inhibiting Drp1-mediated aberrant mitochondrial fission and apoptosis. Collectively, our findings suggest an important molecular mechanism of PD pathogenesis involving ROCK1-regulated dopaminergic nerve cell apoptosis via the activation of Drp1-induced aberrant mitochondrial fission.

ROCK1 promotes migration and invasion of non­small­cell lung cancer cells through the PTEN/PI3K/FAK pathway.

Rho­associated protein kinase 1 (ROCK1), a member of the ROCK family, serves an important function in cell migration and invasion in neoplasms. ROCK1 has been found to be overexpressed in several types of cancers. However, the role of ROCK1 in non­small­cell lung cancer (NSCLC) is poorly understood. In the present study, ROCK1 was found to be overexpressed in NSCLC cells and tissues, and it was associated with poor survival of NSCLC patients. Subsequently, ROCK1 knockdown NSCLC cell lines were established using shRNA. ROCK1 knockdown significantly reduced the migration and invasion ability in the cell monolayer scratching and Transwell assays. ROCK1 knockdown was also found to markedly inhibit cell adhesion ability. Moreover, the phosphorylation of focal adhesion kinase (FAK) was inhibited by ROCK1 knockdown, reducing NSCLC cell migration and invasion ability. This mechanistic study revealed that ROCK1 significantly enhanced cell migration and invasion by inhibiting the phosphatase and tensin homolog (PTEN)/phosphoinositide 3­kinase (PI3K)/FAK pathway. More importantly, the interruption of the PTEN/PI3K/FAK pathway markedly rescued the inhibition of cell migration and invasion mediated by ROCK1 knockdown. Taken together, these results suggest a novel role for ROCK1 in cell migration and invasion by inhibiting cell adhesion ability, and indicate that ROCK1 may be of value as a therapeutic target for the treatment of NSCLC.

Lycorine Induces Mitochondria-Dependent Apoptosis in Hepatoblastoma HepG2 Cells Through ROCK1 Activation.

Lycorine, a naturally occurring compound extracted from the Amaryllidaceae plant family, has been reported to exhibit antitumor activity in various cancer cell types. In the present study, we investigated the molecular mechanisms underlying lycorine-induced apoptosis in hepatoblastoma HepG2 cells. We found that lycorine induced mitochondria-dependent apoptosis in HepG2 cells accompanied by mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential (MMP) loss, adenosine triphosphate (ATP) depletion, Ca2+ and cytochrome c (Cyto C) release, as well as caspase activation. Furthermore, we found Rho associated coiled-coil containing protein kinase 1 (ROCK1) cleavage/activation played a critical role in lycorine-induced mitochondrial apoptosis. In addition, the ROCK inhibitor Y-27632 was employed, and we found that co-treatment with Y-27632 attenuated lycorine-induced mitochondrial injury and cell apoptosis. Meanwhile, an in vivo study revealed that lycorine inhibited tumor growth and induced apoptosis in a HepG2 xenograft mouse model in association with ROCK1 activation. Taken together, all these findings suggested that lycorine induced mitochondria-dependent apoptosis through ROCK1 activation in HepG2 cells, and this may be a theoretical basis for lycorine's anticancer effects.

IR-783 inhibits breast cancer cell proliferation and migration by inducing mitochondrial fission.

IR­783, a near­infrared heptamethine cyanine dye, has been reported to possess cancer targeting and anticancer effects; Ηowever, the molecular mechanism by which IR­783 exhibits anti­breast cancer activity is unclear. In the present study, the inhibitory effects of IR­783 on the proliferation and migration of breast cancer cells were investigated. Our results revealed that IR­783 inhibited MDA­MB­231 and MCF­7 cell proliferation in a dose­ and time­dependent manner by inducing cell cycle arrest at the G0/G1 phase. In addition, a Transwell assay demonstrated that IR­783 treatment suppressed the migratory ability of MDA­MB­231 and MCF­7 cells. Furthermore, IR­783 treatment decreased the expression levels of matrix metalloproteinase (MMP)­2 and MMP­9 in MDA­MB­231 cells. Furthermore, IR­783 induced MDA­MB­231 and MCF­7 cell mitochondrial fission, and also decreased the levels of ATP. This was accompanied with a decrease in polymerized filamentous actin, which is the fundamental component of filopodia at the cell surface. Collectively, the results of the present study demonstrated that IR­783 inhibited the proliferation and migration of MDA­MB­231 and MCF­7 cells by inducing mitochondrial fission and subsequently decreasing ATP levels, resulting in cell cycle arrest and filopodia formation suppression. These findings suggest that IR­783 may be developed into an effective novel drug for treating breast cancer.

Cu2-x Se nanoparticles (Cu2-x Se NPs) mediated neurotoxicity via oxidative stress damage in PC-12 cells and BALB/c mice.

Cu2-x Se nanoparticles (Cu2-x Se NPs) are widely used for optical diagnostic imaging and photothermal therapy due to their strong near-infrared (NIR) optical absorption. With the continuous expansion of applications using Cu2-x Se NPs, their biosafety has received increasing attention in recent years. Cu2-x Se NPs can enter the brain by crossing the blood-brain barrier, but the neurotoxicity of NPs remains unclear. The present investigation provides direct evidence that the toxicity of Cu2-x Se NPs can be specifically exploited to kill rat pheochromocytoma PC-12 cells (a cell line used as an in vitro model for brain neuron research) in dose- and time-dependent manners. These cytotoxicity events were accompanied by mitochondrial damage, adenosine triphosphate (ATP) depletion, production of oxidizing species (including reactive oxygen species (ROS), malondialdehyde (MDA) and hydrogen peroxide (H2O2)), as well as reductions in antioxidant defense systems (glutathione (GSH) and superoxide dismutase (SOD)). Moreover, our in vivo study also confirmed that Cu2-x Se NPs markedly induced neurotoxicity and oxidative stress damage in the striatum and hippocampal tissues of BALB/c mice. These findings suggest that Cu2-x Se NPs induce neurotoxicity in PC-12 cells and BALB/c mice via oxidative stress damage, which provides useful information for understanding the neurotoxicity of Cu2-x Se NPs.

A Review on the Receptor-ligand Molecular Interactions in the Nicotinic Receptor Signaling Systems.

Nicotine is regarded as the main active addictive ingredient in tobacco products driving continued tobacco abuse behavior (smoking) to the addiction behavior, whereas nicotinic acetylcholine receptors (nAChR) is the crucial effective apparatus or molecular effector of nicotine and acetylcholine and other similar ligands. Many nAChR subunits have been revealed to bind to either neurotransmitters or exogenous ligands, such as nicotine and acetylcholine, being involved in the nicotinic receptor signal transduction. Therefore, the nicotinic receptor signalling molecules and the receptor-ligand molecular interactions between nAChRs and their ligands are universally regarded as crucial mediators of cellular functions and drug targets in medical treatment and clinical diagnosis. Given numerous endeavours have been made in defining the roles of nAChRs in response to nicotine and other addictive drugs, this review focuses on studies and reports in recent years on the receptor-ligand interactions between nAChR receptors and ligands, including lipid-nAChR and protein-nAChR molecular interactions, relevant signal transduction pathways and their molecular mechanisms in the nicotinic receptor signalling systems. All the references were carefully retrieved from the PubMed database by searching key words "nicotine", "acetylcholine", "nicotinic acetylcholine receptor(s)", "nAChR*", "protein and nAChR", "lipid and nAChR", "smok*" and "tobacco". All the relevant referred papers and reports retrieved were fully reviewed for manual inspection. This effort intend to get a quick insight and understanding of the nicotinic receptor signalling and their molecular interactions mechanisms. Understanding the cellular receptor-ligand interactions and molecular mechanisms between nAChRs and ligands will lead to a better translational and therapeutic operations and outcomes for the prevention and treatment of nicotine addiction and other chronic drug addictions in the brain's reward circuitry.

Lycorine inhibits cell proliferation and migration by inhibiting ROCK1/cofilin­induced actin dynamics in HepG2 hepatoblastoma cells.

Lycorine, a natural alkaloid extracted from the Amaryllidaceae plant family, has been reported to exhibit anti­cancer effects in various types of cancer cells. However, the molecular mechanisms through which lycorine exhibits anti­hepatoblastoma activity are unclear. In the present study, the inhibitory effects of lycorine on the proliferation and migration of HepG2 hepatoblastoma cells were investigated. Lycorine inhibited the proliferation of HepG2 cells in a dose­dependent manner by inducing cell cycle arrest at the G2/M phase, via downregulation of cyclin A, cyclin B1 and cyclin dependent kinase 1. Additionally, wound healing and Transwell assays revealed that treatment with lycorine resulted in a decrease in the migratory ability of HepG2 cells. Also, treatment with lycorine decreased the expression levels of matrix metalloproteinase (MMP)­9 and MMP­2. Furthermore, lycorine induced the cleavage/activation of Rho associated coiled­coil containing protein kinase 1 (ROCK1) and the downregulation of cofilin, accompanied by an increase in polymerized filamentous actin and a loss of depolymerized globular actin. Furthermore, pre­incubation of cells with Y­27632, a specific ROCK1 inhibitor, markedly attenuated lycorine­induced anti­proliferative and anti­migration effects. Taken together, the results demonstrated that lycorine inhibited the proliferation and migration of HepG2 cells by suppressing ROCK1/cofilin­induced actin dynamics, which suggests that lycorine has the potential to be developed into a novel drug for hepatoblastoma treatment.

Dynamin-related protein 1-mediated mitochondrial fission contributes to IR-783-induced apoptosis in human breast cancer cells.

IR-783 is a kind of heptamethine cyanine dye that exhibits imaging, cancer targeting and anticancer properties. A previous study reported that its imaging and targeting properties were related to mitochondria. However, the molecular mechanism behind the anticancer activity of IR-783 has not been well demonstrated. In this study, we showed that IR-783 inhibits cell viability and induces mitochondrial apoptosis in human breast cancer cells. Exposure of MDA-MB-231 cells to IR-783 resulted in the loss of mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) depletion, mitochondrial permeability transition pore (mPTP) opening and cytochrome c (Cyto C) release. Furthermore, we found that IR-783 induced dynamin-related protein 1 (Drp1) translocation from the cytosol to the mitochondria, increased the expression of mitochondrial fission proteins mitochondrial fission factor (MFF) and fission-1 (Fis1), and decreased the expression of mitochondrial fusion proteins mitofusin1 (Mfn1) and optic atrophy 1 (OPA1). Moreover, knockdown of Drp1 markedly blocked IR-783-mediated mitochondrial fission, loss of MMP, ATP depletion, mPTP opening and apoptosis. Our in vivo study confirmed that IR-783 markedly inhibited tumour growth and induced apoptosis in an MDA-MB-231 xenograft model in association with the mitochondrial translocation of Drp1. Taken together, these findings suggest that IR-783 induces apoptosis in human breast cancer cells by increasing Drp1-mediated mitochondrial fission. Our study uncovered the molecular mechanism of the anti-breast cancer effects of IR-783 and provided novel perspectives for the application of IR-783 in the treatment of breast cancer.