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Phytomedicine

Phytomedicine

IF: 6.7
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Andrographolide suppresses the malignancy of pancreatic cancer via alleviating DNMT3B-dependent repression of tumor suppressor gene ZNF382

Published:4 July 2024 DOI: PMID: 38991252
Kai-Ru Zhuang , Chian-Feng Chen , Hsin-Yu Chan , Shin-E Wang , Dai-Heng Lee , Shih-Chin Chen , Bor-Uei Shyr , Yi-Ju Chou , Chiao-Che Chen , Shao-Ho Yuan , Yuan-I Chang , Hsueh-Te Lee , Shu-Ling Fu

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type that urgently requires effective therapeutic strategies. Andrographolide, a labdane diterpenoid compound abundant in Andrographis paniculata, has anticancer effects against various cancer types, but its anticancer activity and mechanism against PDAC remain largely uncharacterized.

Purpose

This study explores novel drug target(s) and underlying molecular mechanism of andrographolide against PDAC.

Study design and methods

The malignant phenotypes of PDAC cells, PANC-1 and MIA PaCa-2 cells, were measured using MTT, clonogenic assays, and Transwell migration assays. A PDAC xenograft animal model was used to evaluate tumor growth in vivo. Western blot, immunofluorescence and immunohistochemistry were used for measuring protein expression. The TCGA database was analyzed to evaluate promoter methylation status, gene expression, and their relationship with patient survival rates. RT-qPCR was used for detecting mRNA expression. Reporter assays were used for detecting signal transduction pathways. Promoter DNA methylation was determined by sodium bisulfite treatment and methylation-specific PCR (MSP). The biological function and role of specific genes involved in drug effects were measured through gene overexpression.

Results

Andrographolide treatment suppressed the proliferation and migration of PDAC cells and impaired tumor growth in vivo. Furthermore, andrographolide induced the mRNA and protein expression of zinc finger protein 382 (ZNF382) in PDAC cells. Overexpression of ZNF382 inhibited malignant phenotypes and cancer-associated signaling pathways (AP-1, NF-κB and β-catenin) and oncogenes (ZEB-1, STAT-3, STAT-5, and HIF-1α). Overexpression of ZNF382 delayed growth of PANC-1 cells in vivo. ZNF382 mRNA and protein expression was lower in tumor tissues than in adjacent normal tissues of pancreatic cancer patients. Analysis of the TCGA database found the ZNF382 promoter is hypermethylated in primary pancreatic tumors which correlates with its low expression. Furthermore, andrographolide inhibited the expression of DNA methyltransferase 3 beta (DNMT3B) and increased the demethylation of the ZNF382 promoter in PDAC cells. Overexpression of DNMT3B attenuated the andrographolide-suppressed proliferation and migration of PDAC cells.

Conclusion

Our finding revealed that ZNF382 acts as a tumor suppressor gene in pancreatic cancer and andrographolide restores ZNF382 expression to suppress pancreatic cancer, providing a novel molecular target and a promising therapeutic approach for treating pancreatic cancer.

Substances (16)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Gemcitabine hydrochloride 122111-03-9 C9H11F2N3O4.ClH 796 suppliers $4.00-$8990.00
Gemcitabine hydrochloride 122111-03-9 C9H11F2N3O4.ClH 796 suppliers $4.00-$8990.00
Gemcitabine hydrochloride 122111-03-9 C9H11F2N3O4.ClH 796 suppliers $4.00-$8990.00
Gemcitabine hydrochloride 122111-03-9 C9H11F2N3O4.ClH 796 suppliers $4.00-$8990.00
5-Aza-2'-deoxycytidine 2353-33-5 C8H12N4O4 747 suppliers $8.00-$2480.00
5-Aza-2'-deoxycytidine 2353-33-5 C8H12N4O4 747 suppliers $8.00-$2480.00
5-Aza-2'-deoxycytidine 2353-33-5 C8H12N4O4 747 suppliers $8.00-$2480.00
5-Aza-2'-deoxycytidine 2353-33-5 C8H12N4O4 747 suppliers $8.00-$2480.00
Gemcitabine HCl 122111-03-9 - Inquiry
Gemcitabine HCl 122111-03-9 - Inquiry

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