Lentinan-functionalized Selenium Nanoparticles target Tumor Cell Mitochondria via TLR4/TRAF3/MFN1 pathway

Abstract

Rationale: Malignant ascites caused by cancer cells results in poor prognosis and short average survival time. No effective treatment is currently available for malignant ascites. In this study, the effects of lentinan (LNT)-functionalized selenium nanoparticles (Selene) on malignant ascites were evaluated. Furthermore, the mechanism of Selene targeting mitochondria of tumor cells were also investigated. Methods: Selene were synthesized and characterized by TEM, AFM and particle size analysis. The OVCAR-3 and EAC cells induced ascites models were used to evaluate the effects of Selene on malignant ascites. Proteomic analysis, immunofluorescence, TEM and ICP-MS were used to determine the location of Selene in tumor cells. Mitochondrial membrane potential, ROS, ATP content, and caspase-1/3 activity were detected to evaluate the effect of Selene on mitochondrial function and cell apoptosis. Immunofluorescence, Co-IP, pull-down, duolink, Western blot, and FPLC were used to investigate the pathway of Selene targeting mitochondria. Results: Selene could effectively inhibit ascites induced by OVCAR-3 and EAC cells. Selene was mainly located in the mitochondria of tumor cells and induced apoptosis of tumor cells. The LNT in Selene was involved in caveolae-mediated endocytosis through the interaction between toll-like receptor-4 (TLR4) and caveolin 1 (CAV1). Furthermore, the Selene in the endocytic vesicles could enter the mitochondria via the mitochondrial membrane fusion pathway, which was mediated by TLR4/TNF receptor associated factor 3 (TRAF3)/mitofusin-1 (MFN1) protein complex. Conclusion: Selene is a candidate anticancer drug for the treatment of malignant ascites. And TLR4/TRAF3/MFN1 may be a specific nano-drug delivery pathway that could target the mitochondria.

MS275 as Class I HDAC inhibitor displayed therapeutic potential on malignant ascites by iTRAQ-based quantitative proteomic analysis

“…To study the selective toxicity of different isoform-selective HDACIs on ascites cells, the class I selective HDACI MS275, the class II selective HDACI MC1568 and the broad-spectrum HDACI SAHA were chosen to test the cytotoxicity to ascites cells. Because primary peritoneal carcinoma is rare [ 20 , 21 ] and malignant ascites are mainly originated from different metastatic peritoneal carcinoma, here we chose 3 different ascites cell. S180, H22 and EAC are murine sarcoma cancer cell, murine hepatocarcinoma cell, and murine mammary adenocarcinoma cell respectively, and the related ascites model induced by these cells are commonly used [ 21 , 22 ].…”

“…Because primary peritoneal carcinoma is rare [ 20 , 21 ] and malignant ascites are mainly originated from different metastatic peritoneal carcinoma, here we chose 3 different ascites cell. S180, H22 and EAC are murine sarcoma cancer cell, murine hepatocarcinoma cell, and murine mammary adenocarcinoma cell respectively, and the related ascites model induced by these cells are commonly used [ 21 , 22 ]. As shown in Fig.…”

Selenium Nanoparticles for Biomedical Applications: From Development and Characterization to Therapeutics

“…Lentinan‐SeNPs act by enhancing ROS and decreasing the mitochondrial membrane potential, thereby inducing caspase‐3 expression and reduction of ATP levels, while decreasing the expression of several inflammatory cytokines (IL‐1 β , IL‐6, and TNF‐ α ), which led to cell shrinkage and formation of apoptotic bodies. [ 227 ] The anticancer properties of SeNPs stabilized with another fungus polysaccharide, PUP, were also studied. PUP‐SENPs successfully inhibited several cancer cell lines (HT29, HeLa, HepG2, and MDA‐MB‐231) proliferation in a dose‐dependent manner, with no apparent toxicity towards normal cells.…”

Proteomic Research on the Antitumor Properties of Medicinal Mushrooms

“…Liu et al [120] studied the effects of lentinan (LNT)-functionalized selene nanoparticles on malignant ascites. Ovarian malignancy is the most common cause of malignant ascites, which is why OVCAR-3 human ovarian cancer cells were used in this study, along with EAT, a common tumor ascites model [121].…”

“…In contrast to SeNP, which induced pyroptosis because of being taken up by lysosomes, it was shown that Selene was mainly taken up by the mitochondria, thereby inhibiting inflammatory cytokine secretion in ascites. The authors concluded that Selene is effective for treating malignant ascites and may be developed as a clinical drug [120].…”