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Proteomic studies of the mechanism of cytotoxicity, induced by palytoxin on HaCaT cells

ABSTRACT: Palytoxin (PLTX) is a polyether Marine toxin isolated from sea anemones. It is one of the most toxic non-protein substances, causing many people to be poisoned every year and die in severe cases. With its known impact on Na+, K+-ATPase, much still remain unclear about the mechanism of PLTX action. Here, we tested different concentrations of PLTX on HaCaT cells, and studied its distributions in cells, its impact on gene expressions, and associated pathways using proteomics combined with bioinformatics tools. We found that PLTX could cause ferroptosis in HaCaT cells, a new type of programmed cell death, by up-regulating the expressions of VDAC3, ACSL4, and NCOA4 that lead to the occurrence of ferroptosis. PLTX also acts on MAPK pathway that is related to cell apoptosis, proliferation, division and differentiation. Different from that of ferroptosis, PLTX down-regulates the expression of ERK, and as a result, the expressions of MAPK1, MAP2K1 and MAP2K2 are also lower which will affect cell proliferation. The genes from these two mechanisms showed interactions but we didn’t find overlap genes between the two. Both ferroptosis and MAPK pathways can be used as anticancer targets, so PLTX may become an anticancer drug with appropriate modification.

ORGANISM(S): Homo Sapiens

SUBMITTER: Minjuan Sun

PROVIDER: PXD032777 | iProX | Thu Mar 24 00:00:00 GMT 2022

REPOSITORIES: iProX

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Proteomic Studies of the Mechanism of Cytotoxicity, Induced by Palytoxin on HaCaT Cells.

Cheng Dingyuan D Deng Bowen B Tong Qiling Q Gao Siyi S Xiao Boyi B Zhu Mengxuan M Ren Ziyu Z Wang Lianghua L Sun Mingjuan M

Toxins 20220410 4

Palytoxin (PLTX) is a polyether marine toxin isolated from sea anemones. It is one of the most toxic nonprotein substances, causing many people to be poisoned every year and to die in severe cases. Despite its known impact on Na<sup>+</sup>,K<sup>+</sup>-ATPase, much still remains unclear about PLTX's mechanism of action. Here, we tested different concentrations of PLTX on HaCaT cells and studied its distributions in cells, its impact on gene expression, and the associated pathways via proteomic ...[more]

PMID: 35448878

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Project description:In hepatocellular carcinoma (HCC) development, cancer cells generally exhibit increased cell proliferation due to mutations and aberrant expressions of key regulatory genes. The current study determines the cytotoxic effects of β-caryophyllene (BCP) alone or in combination with doxorubicin (DOX) and cisplatin (DDP) on HCC cells and also elucidates the underlying mechanism of BCP to exert its anticancer activities. HepG2, SMMC-7721 HCC cells, and HL-7702 normal liver cells were treated with BCP, DOX, and DDP individually or in their combinations. Cell proliferation assay, flow cytometric assay, and Western blot analysis were used to evaluate the cytotoxic effects of these treatments. Transwell assays were used to examine the effects of BCP on migration and invasion of HCC cells. RNA-seq studies were used to determine the primary target genes of BCP-treated HepG2 cells. Integrative analysis of differentially expressed genes (DEGs) of RNA-seq data with a TCGA dataset of HCC patients identified BCP-targeted genes that were verified by RT-qPCR. Ectopic gene expression, cell viability, and colony formation assay were performed to validate the primary targets of BCP. The results found that, BCP selectively inhibited HCC cell proliferation while exhibited relatively low toxicity to normal liver cells; however, DOX and DDP showed higher toxicity in normal cells than that in HCC cells. Importantly, in combinatorial treatments, BCP synergistically enhanced cytotoxicity of DOX and DDP in HCC cells but this effect is markedly reduced in HL-7702 cells. BCP-treated HCC cells exhibited decreased migration and invasion ability versus the control. Furthermore, RNA-seq analyses of BCP-treated HepG2 cells identified 433 protein-coding DEGs with over 1.5-fold change. Integrative analyses revealed five BCP-targeted DEGs regulating the MAPK signaling pathway. Among these five genes, three displayed a significantly positive correlation of their expression with the overall survival of HCC patients. As a primary target, PGF was significantly downregulated by BCP treatment, and its exogenous expression desensitized HCC cells to the inhibition of BCP treatment. In summary, BCP inhibits malignant properties of HCC and synergistically sensitizes the anticancer activity of DOX and DDP. In HCC cells, BCP primarily targets PGF and MAPK signaling pathway.

Dataset Information

Proteomic studies of the mechanism of cytotoxicity, induced by palytoxin on HaCaT cells

Publications

Proteomic Studies of the Mechanism of Cytotoxicity, Induced by Palytoxin on HaCaT Cells.

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