Carboplatin is the most commonly used drug in the first-line treatment of human retinoblastoma (RB), but its clinical application is greatly limited due to acquired drug resistance upon the long-term treatment. Forkhead box protein M1 (FoxM1) is the transcription factor aberrantly expressed in various types of human cancers, which plays an essential role in the regulation of tumorigenesis, tumor metastasis and drug resistance. However, little is known about the role of FoxM1 in chemo-resistance of human RB. In this study, we investigated the regulatory effect of FoxM1 on carboplatin resistance in human RB Y-79 cells and carboplatin-resistant Y-79 (Y-79CR) cells, as well as the possible mechanism. Our results showed that FoxM1 was up-regulated in Y-79CR cells and silencing of FoxM1 promoted carboplatin sensitivity and accumulation, while overexpression of FoxM1 in Y-79 cells performed oppositely. Our study further revealed that FoxM1 enhanced carboplatin resistance in Y-79CR cells through directly up-regulating the transcription of ATP-binding cassette transporter C4 (ABCC4), an important drug efflux transporter. Overall, our study demonstrated the novel role of FoxM1-ABCC4 axis in human RB, which provides insights into the prevention of carboplatin resistance in human RB.

Ziyuglycoside I (Ziyu I), one of the major components isolated from the root of Sanguisorba officinalis L., has been proved for the antitumor properties on oral cancer, prostate cancer, and colorectal cancer. However, the effect of Ziyu I on retinoblastoma (RB) is not well understood. In this study, we investigated the inhibitory effect and underlying molecular mechanism of Ziyu I on human RB WERI‐Rb‐1 cells. Our results indicated that Ziyu I could suppress cell viability and induce mitochondrial‐dependent cell apoptosis in WERI‐Rb‐1 cells. Furthermore, Ziyu I treatment increased p53 expression as well as improved p53 stabilization through downregulation of pS166‐Mdm2 and upregulation of phosphorylated‐ and acetylated‐p53. Blockade of p53 significantly attenuated Ziyu I‐induced mitochondrial dysfunction. Our findings demonstrate that Ziyu I exhibits excellent anticancer effect on human RB WERI‐Rb‐1 cells by triggering p53 activation, and imply Ziyu I as a potential compound for chemotherapy of human RB.

Retinoblastoma (Rb) is the most frequent primary intraocular tumor usually diagnosed in infants and children, and current therapy for such disease is still limited. Corosolic acid (CA), an ursane-type pentacyclic triterpene, has been assessed as a promising anticancer agent with little impact on untransformed cells. In the present study, we investigated the cytotoxic effect and underlying mechanism of CA on human retinoblastoma Y-79 cells. The viability of cells was verified by MTT assay. Cell cycle and apoptosis were evaluated by flow cytometric analysis. The expressions and activities of the related molecules were assessed by western blot analysis and luciferase assay. The results demonstrated that the treatment of CA dose-dependently induced cytotoxicity, cell cycle arrest and cell apoptosis in Y-79 cells. Furthermore, MELK-FoxM1 signaling was estimated to be involved in the cytotoxic effect of CA on Y-79 cells, and CA exerted its activity mainly through inhibition of the expression levels of MELK and FoxM1 as well as through suppression of the transcriptional activity of FoxM1 driven by itself or MELK. Our findings establish MELK-FoxM1 signaling as a promising therapeutic target for human retinoblastoma, and suggest the potential development of CA and its derivatives as novel drug candidates against this disease.