Talks
Presenting Author Academic/Professional Position
Faculty
Academic Level (Author 1)
Faculty
Discipline/Specialty (Author 1)
Immunology and Microbiology
Academic Level (Author 2)
Post-doc
Discipline/Specialty (Author 2)
Immunology and Microbiology
Academic Level (Author 3)
Post-doc
Presentation Type
Oral Presentation
Discipline Track
Biomedical Science
Abstract Type
Research/Clinical
Abstract
Background: Cervical cancer (CxC) is a leading cause of mortality and morbidity among women worldwide. Current chemotherapeutic agents for CxC have shown systemic toxicity in CxC patients. Ormeloxifene (ORM) is a non-toxic and non-steroidal drug with well-defined pharmacokinetic and pharmacodynamic properties in humans. Studies have shown its anticancer potential in various pre-clinical mouse models. Here, we have synthesized and characterized a novel analogue of ormeloxifene, Bromo-ormeloxifene (Br-ORM), which showed more therapeutic efficacy against CxC in vitro and in vivo model systems.
Methodology: The effect of Br-ORM on CxC cells (CaSki and SiHa) growth and proliferation was determined by colony formation and MTS assays. Molecular docking of Br-ORM with β-catenin was done by AutoDock4 software. Effect of Br-ORM on the expression of epithelial-to mesenchymal (EMT) markers (N-cadherin, slug, snail), MMPs (MMP2 and MMP3) and miR-200a were analyzed by Western blot and qPCR analyses respectively. Apoptosis analysis was done by Annexin-V staining kit. Effect of Br-ORM on β-catenin cellular localization in CxC cells was analyzed by immunofluorescence analysis. The anti-tumor efficacy of Br-ORM was investigated in orthotopic xenograft mouse model of CxC.
Results: Br-ORM effectively inhibited growth and proliferation of CxC cells in a dose and timedependent manner as compared to ORM. Br-ORM efficiently suppressed metastatic phenotypes of CxC cells as determined by significant (P<0.05) decrease in invasion and migration potential of CxC cells. Moreover, Br-ORM showed increased apoptosis, which was observed by enhanced Annexin-V staining and PARP protein cleavage. Br-ORM markedly reduced the EMT process as evident by repression of N-cadherin, slug, snail, MMPs and β-catenin/TCF-4 transcriptional activity. Br-ORM potently reduced the translocation of β-catenin in the nucleus. Bioinformatic analysis revealed that Br-ORM proficiently binds into active site of β-catenin with a minimum energy -7.6 kcal/mol. Br-ORM treatment replenished the expression of miR-200a, which directly targets β-catenin in CxC cells. Br-ORM significantly (P<0.01) regressed the cervical tumor growth in orthotopic xenograft mouse model. Similar molecular effects of Br-ORM were observed in excised tumor tissues.
Conclusion: These results suggest that Br-ORM inhibits the metastatic phenotypes of CxC cells via targeting β-catenin signaling pathway. Br-ORM could be used as a novel therapeutic modality for the treatment of CxC.
Recommended Citation
Sikander, Mohammed; Malik, Shabnam; Kumari, Sonam; Khan, Sheema; Apraku, John; Ganju, Aditya; Khan, Parvez; Halaweish, Fathi T.; Yallapu, Murali; Jaggi, Meena; and Chauhan, Subhash, "Novel analogue of Ormeloxifene Suppresses Epithelial-Mesenchymal Transition by Disrupting β-Catenin Signaling in Cervical Cancer" (2025). Research Symposium. 22.
https://scholarworks.utrgv.edu/somrs/2025/talks/22
Novel analogue of Ormeloxifene Suppresses Epithelial-Mesenchymal Transition by Disrupting β-Catenin Signaling in Cervical Cancer
Background: Cervical cancer (CxC) is a leading cause of mortality and morbidity among women worldwide. Current chemotherapeutic agents for CxC have shown systemic toxicity in CxC patients. Ormeloxifene (ORM) is a non-toxic and non-steroidal drug with well-defined pharmacokinetic and pharmacodynamic properties in humans. Studies have shown its anticancer potential in various pre-clinical mouse models. Here, we have synthesized and characterized a novel analogue of ormeloxifene, Bromo-ormeloxifene (Br-ORM), which showed more therapeutic efficacy against CxC in vitro and in vivo model systems.
Methodology: The effect of Br-ORM on CxC cells (CaSki and SiHa) growth and proliferation was determined by colony formation and MTS assays. Molecular docking of Br-ORM with β-catenin was done by AutoDock4 software. Effect of Br-ORM on the expression of epithelial-to mesenchymal (EMT) markers (N-cadherin, slug, snail), MMPs (MMP2 and MMP3) and miR-200a were analyzed by Western blot and qPCR analyses respectively. Apoptosis analysis was done by Annexin-V staining kit. Effect of Br-ORM on β-catenin cellular localization in CxC cells was analyzed by immunofluorescence analysis. The anti-tumor efficacy of Br-ORM was investigated in orthotopic xenograft mouse model of CxC.
Results: Br-ORM effectively inhibited growth and proliferation of CxC cells in a dose and timedependent manner as compared to ORM. Br-ORM efficiently suppressed metastatic phenotypes of CxC cells as determined by significant (P<0.05) decrease in invasion and migration potential of CxC cells. Moreover, Br-ORM showed increased apoptosis, which was observed by enhanced Annexin-V staining and PARP protein cleavage. Br-ORM markedly reduced the EMT process as evident by repression of N-cadherin, slug, snail, MMPs and β-catenin/TCF-4 transcriptional activity. Br-ORM potently reduced the translocation of β-catenin in the nucleus. Bioinformatic analysis revealed that Br-ORM proficiently binds into active site of β-catenin with a minimum energy -7.6 kcal/mol. Br-ORM treatment replenished the expression of miR-200a, which directly targets β-catenin in CxC cells. Br-ORM significantly (P<0.01) regressed the cervical tumor growth in orthotopic xenograft mouse model. Similar molecular effects of Br-ORM were observed in excised tumor tissues.
Conclusion: These results suggest that Br-ORM inhibits the metastatic phenotypes of CxC cells via targeting β-catenin signaling pathway. Br-ORM could be used as a novel therapeutic modality for the treatment of CxC.
