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Daphnetin sensitizes hepatocellular carcinoma cells to chemotherapeutics and suppresses malignant phenotypes through modulating DDIT3-associated stress-response

ABSTRACT: Many natural products can both suppress tumor growth and promote human health. Daphnetin (DAP) is a natural coumarin and possesses suppressive activities against various cancers, but the molecular mechanisms underlying its anticancer action remain poorly understood. In the treatments of hepatocellular carcinoma (HCC), many generic chemotherapeutic agents, such as doxorubicin (DOX) and cisplatin (DDP), manifest significant side effects on patients. In the present study, we first investigated the cytotoxic effects of DAP alone or in combination with DOX or DDP in HCC HepG2 and SMMC-7721 cells, and in normal liver HL-7702 cells. Based on isobologram analysis, DAP synergistically enhanced cytotoxic activities of DDP and DOX in HCC cells but not in HL-7702 cells. RNA-seq analysis of DAP-treated HepG2 cells identified 484 protein-coding DEGs involved in multiple pathways, such as PI3K-AKT signaling, amino acid deprivation, and unfolded protein response. Especially, DAP treatment upregulated a stress-responsive pro-apoptotic transcription factor DDIT3. Consistently, DDIT3 knockdown desensitized HCC cells to DAP, while constitutively active AKT did not rescue DAP-induced defective phenotypes. Collectively, we demonstrate DAP as a multi-pathway stress-modulating agent that can both attenuate malignant phenotypes of HCC cells and sensitize the cells to clinical chemotherapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE315518 | GEO | 2026/01/08

REPOSITORIES: GEO

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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.

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Daphnetin sensitizes hepatocellular carcinoma cells to chemotherapeutics and suppresses malignant phenotypes through modulating DDIT3-associated stress-response

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