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Dihydroartemisinin Affects STAT3/DDA1 Signaling Pathway and Reverses Breast Cancer Resistance to Cisplatin
Jing Zhang1,2, Yang Li2, Ji-Guo Wang2
1The First School of Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China.
Abstract:
Dihydroartemisinin (DHA) has anticancer effects on multiple tumors, including those associated with breast cancer. This study aimed to investigate the mechanism causing DHA-reversing cisplatin (DDP) resistance in breast cancer. Relative mRNA and protein levels were tested using a qRT-PCR and western blot assay. Cell proliferation, viability, and apoptosis were evaluated using colony formation, MTT, and flow cytometry assays, respectively. Interaction of STAT3 and DDA1 was measured via a dual-luciferase reporter assay. The results showed that DDA1 and p-STAT3 levels were dramatically elevated in DDP-resistant cells. DHA treatment repressed proliferation and induced apoptosis of DDP-resistant cells by suppressing STAT3 phosphorylation; the inhibition ability was positively proportional to the DHA concentration. DDA1 knockdown inhibited cyclin expression, promoted G0/G1 phase arrest, restrained cell proliferation, and induced apoptosis of DDP-resistant cells. Furthermore, knockdown of STAT3 restrained proliferation and induced apoptosis and G0/G1 cell cycle arrest of DDP-resistant cells by targeting DDA1. DHA could restrain tumor proliferation of breast cancer via enhancing drug sensitivity of DDP-resistant cells through the STAT3/DDA1 signaling pathway.
Insights
Dihydroartemisinin (DHA) reverses cisplatin resistance in breast cancer by targeting the STAT3/DDA1 pathway. This enhances drug sensitivity and suppresses tumor growth, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Dihydroartemisinin (DHA) exhibits anticancer properties in various tumors, including breast cancer.
- Cisplatin (DDP) resistance is a significant challenge in breast cancer treatment.
- The underlying mechanisms of DHA's efficacy in overcoming DDP resistance require elucidation.
Purpose of the Study:
- To investigate the molecular mechanism by which DHA reverses cisplatin resistance in breast cancer.
- To explore the role of the STAT3/DDA1 signaling pathway in this process.
Main Methods:
- Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting for gene and protein expression.
- Cell proliferation, viability, and apoptosis assays (colony formation, MTT, flow cytometry).
- Dual-luciferase reporter assay to assess STAT3 and DDA1 interaction.
Main Results:
- DDA1 and phosphorylated STAT3 (p-STAT3) levels were elevated in DDP-resistant breast cancer cells.
- DHA treatment suppressed proliferation and induced apoptosis in DDP-resistant cells by inhibiting STAT3 phosphorylation.
- DDA1 knockdown or STAT3 knockdown individually hindered proliferation and promoted apoptosis and G0/G1 cell cycle arrest in DDP-resistant cells.
- DHA enhances drug sensitivity in DDP-resistant cells via the STAT3/DDA1 pathway.
Conclusions:
- DHA overcomes cisplatin resistance in breast cancer by downregulating the STAT3/DDA1 signaling pathway.
- Targeting STAT3 or DDA1 could be a therapeutic strategy to sensitize breast cancer to cisplatin.
