Targeted inhibition of JMJD2C/MALAT1 axis compensates for the deficiency of metformin in reversing ovarian cancer platinum resistance
Abstract
AIMS: We explored JMJD2C's role in platinum resistance in ovarian cancer and its modulation by metformin to propose strategies for overcoming treatment limitations.
MATERIALS AND METHODS: JMJD2C and MALAT1 expression was assessed via RT-qPCR, western blotting, and immunohistochemical assays using OC cell lines, tissue from OC patients, and xenograft treatment with or without metformin. CCK-8 assays, flow cytometry, inductively coupled plasma mass spectrometry, luciferase reporter assays, and ChIP assays were employed to evaluate the impact of JMJD2C/MALAT1 on PR and the effects of metformin on JMJD2C. The effects of metformin in combination with JMJD2C knockdown were assessed in vitro and in vivo.
KEY FINDINGS: JMJD2C and MALAT1 expression was higher in tissue samples from platinum-resistant phase compared to those from paired platinum-sensitive phase. JMJD2C upregulated MALAT1 in platinum-resistant ovarian cancer (PROC) cells by demethylating its promoter at sites H3K9m3 and H3K36m3. Overexpression of JMJD2C or MALAT1 promoted PR by activating NF-κB/P-gp and P38 MAPK/ERCC1 signaling pathways, with their knockdown produced the opposite effect. Metformin increased JMJD2C expression in tumor tissue, cell lines, and a xenograft model of OC; however, elevated JMJD2C expression attenuated the PR-reversal efficacy of low-concentration metformin. Low-dose metformin combined with JMJD2C-knockdown effectively reversed PR both in in vitro and in vivo, achieving better results than…
Read the paper
Related studies
- Metformin as an adjuvant in breast cancer treatment
- Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
- Aberrant HSF1 signaling activation underlies metformin amelioration of myocardial infarction in mice
- Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines
- Protein Interaction Network for Identifying Vascular Response of Metformin (Oral Antidiabetic)
- Preventing Long COVID With Metformin
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.