This work is performed to investigate the effect of coptisine (COP) on the malignant biological behaviors of bladder carcinoma cells and its underlying mechanism. Bladder carcinoma cell lines were treated with different concentrations of COP in vitro. Cell counting kit-8 (CCK-8), scratch healing assay, Transwell assay, and flow cytometry were used to detect cell growth, migration, invasion, and cell cycle progression. Bioinformatics analysis was performed to predict the molecular targets of COP. Quantitative real-time PCR and western blot were adopted to determine the expression levels of exportin 1 (XPO1) mRNA and protein, respectively. Gene set enrichment analysis was applied to predict the signaling pathways related to XPO1. This study showed that COP treatment markedly suppressed the malignant biological behaviors of bladder carcinoma cells. XPO1 was identified as a downstream molecular target of COP in bladder carcinoma, and COP treatment inhibited the expression of XPO1 in bladder carcinoma cell lines. Overexpression of XPO1 reversed the impacts of COP on the malignant biological behaviors of bladder carcinoma cells. COP treatment modulated the expression level of cyclin D1 and CYP450 via XPO1. In summary, COP represses the malignant biological behaviors of bladder carcinoma cells and regulates XPO1 expression, which is promising to be a complementary drug for bladder carcinoma treatment.
Abstract Cisplatin is a cornerstone chemotherapeutic for ovarian cancer, yet its clinical utility is constrained by severe systemic toxicity and acquired drug resistance. Here we report a novel platinum (IV) prodrug, US-CIS-OH, generated by conjugating cisplatin with ursolic acid (UA), a natural pentacyclic triterpenoid with intrinsic anticancer activity. US-CIS-OH, markedly increases platinum uptake and DNA platination in cisplatin-resistant ovarian cancer cells, induces S- and G2/M-phase arrest and apoptosis, and suppresses cell migration and clonogenic growth. Chemoproteomic profiling indicates that US-CIS-OH directly engages the XPO1 and PARP1, and is associated with increased levels of cleaved caspase-3. In a cisplatin-resistant ovarian cancer xenograft model, US-CIS−OH elicits marked tumor regression with minimal toxicity. This dual-acting system achieves synergistic effects from both the intact conjugated and bioreductively released cisplatin. Collectively, these results identify US-CIS−OH as a promising next-generation platinum-based agent to overcome cisplatin resistance by enhancing DNA damage, promoting apoptosis, and limiting metastatic traits.
Objective Cancer stem cells (CSCs) are responsible for cervical cancer progression and decreased radiosensitivity of tumor cells. Thepresent work is meant to illuminate the impacts of exportin 1 (XPO1) on the aggressive behaviors and radiosensitivity of cervicalcancer stemness cells and make a deeper inquiry into its regulatory mechanism despite that XPO1 has been supported to elicitsignificant activities on multiple malignancies. Methods XPO1 and Rad21 expression in HeLa (CD44+) cells was tested by RT-qPCR and western blot. Cell viability was estimated via CCK-8 assay. Cell stemness was examined viasphere formation assay and western blot. Following radiation treatment, cell proliferation was judged by CCK-8 assay, westernblot as well as EdU staining whereas TUNEL assay, RT-qPCR and western blot analysis appraised cell apoptosis. Cell radiosensitivitywas assessed through clonogenic survival assay. The levels of DNA damage markers were tested by western blot and related kits.STRING database and Co-IP assay respectively predicted and testified the binding of XPO1 with Rad21. RT-qPCR and western blotalso examined the expression of XPO1 cargoes. Results The experimental data corroborated that XPO1 and Rad21 were overexpressed in cervical cancer tissues and cells. XPO1 inhibitorKPT-330 impeded the stemness while elevated the radiosensitivity of HeLa (CD44+) cells. XPO1 bond to Rad21 and positively modulated Rad21 expression. Moreover, Rad21 elevation reversed the impacts of KPT-330on the behaviors of cervical cancer stemness cells. Conclusion To sum up, XPO1 might impact the aggressive behavior and radioresistance of cervical cancer stemness cells through bindingwith Rad21.
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