Integrated transcriptomic and functional analysis reveals selective cytotoxicity and HPV oncogene suppression induced by cinnamon essential oil in cervical cancer cells

Abstract

Cervical cancer (CC) remains a major cause of cancer-related mortality among women worldwide, primarily driven by persistent infection with high-risk human papillomavirus (HPV) types. Given that natural products with selective antitumour properties offer potential for novel therapies, we evaluated the cytotoxic, antiproliferative, and molecular effects of cinnamon essential oil (CEO) on HPV-positive cervical cancer cell lines (HeLa and SiHa) and nontumorigenic keratinocytes (HaCaT). Cells were exposed to a range of dilutions of CEO. Cell viability was determined by WST-1 and sulforhodamine B assays. Apoptosis was assessed using Annexin V/PI staining, caspase-3/8/9 activation, and mitochondrial membrane potential (Δψm) loss by flow cytometry. Proliferation was measured using EdU incorporation, and senescence was measured by β-galactosidase activity. Genome-wide transcriptional changes and HPV E6/E7 oncogene expression were analysed by RNA-Seq and validated with qPCR. CEO induced dose-dependent cytotoxicity and inhibited proliferation in cervical cancer cells, while HaCaT cells were significantly more resistant. Apoptosis was evidenced by Annexin V/PI positivity, activation of caspases -8, -9, and -3, and significant loss of mitochondrial membrane potential. No significant senescence induction was observed. Additionally, CEO also significantly downregulated HPV E6 / E7 oncogene expression in HeLa and SiHa cells. Transcriptomic analysis revealed broad differential gene expression, including upregulation of stress and apoptosis-related genes and downregulation of proliferation, oxidative phosphorylation, and viral-related pathways. CEO exerts selective cytotoxic and antiproliferative effects on cervical cancer cells by triggering mitochondria-mediated apoptosis and suppressing HPV oncogenes. These findings support CEO as a potential source of bioactive compounds for complementary strategies against HPV-related malignancies.