Desmoglein 2 is associated with dihydroartemisinin resistance in HeLa cervical cancer cells: a potential link to the PI3K/AKT signaling pathway

The primary challenges in the clinical treatment of cervical cancer include metastasis, recurrence, proliferation, and drug resistance. DSG2 is a transmembrane desmosomal cadherin, has been implicated in various cancers, but its specific role in cervical cancer remains unclear.Recently, Dihydroartemisinin (DHA) has emerged as a promising antitumor drug. In this study, we aimed to investigate the impact of DSG2 on cervical cancer cells treated with DHA. Cellular assays demonstrated that DHA effectively inhibited the proliferation, migration, and invasion of HeLa cells. Increasing concentrations of DHA prolonged its effects and reduced HeLa cell proliferation. RNA-seq analysis revealed that DHA induced differential gene expression involved in cell migration, protein digestion and absorption, cytokine receptor interaction, the PI3K/AKT signaling pathway, and the Rap1 signaling pathway. DHA downregulated the expression of PI3K and AKT, while upregulating P53, ATM, cleaved caspase-3, and H2AX expression. Overexpression of DSG2 in HeLa cells increased resistance to DHA inhibition, whereas knockdown of DSG2 enhanced the inhibitory effects of DHA. This study highlights that DSG2 modulates the cytotoxicity of DHA, which is potentially associated with the PI3K/AKT signaling pathway, suggesting DSG2 as a candidate biomarker and a potential target for further investigation in cervical cancer. This study investigates how DSG2, a poor prognostic marker in cervical cancer, attenuates dihydroartemisinin (DHA)-mediated HeLa cell proliferation inhibition via the PI3K/AKT pathway. Key findings show DSG2 overexpression reduces DHA sensitivity, while knockdown enhances it linking DSG2 to DHA resistance. These results suggest DSG2 as a potential biomarker and a candidate target for further investigation to improve DHA’s anticancer efficacy, addressing critical clinical challenges of cervical cancer proliferation and drug resistance.