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Identification and clinical prognosis of salinomycin binding targets in neuroblastoma (LB613)
Author(s) -
Zhou Shuang,
Wang Fengfei,
Xiang Shihua,
Wong Eric,
Muhonen Wallace,
Fonkem Ekokobe,
Hsieh Tzechen,
Li David,
Zhang Ruiwen,
Shabb John,
Wu Joseph,
Wu Min,
Wu Erxi
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.lb613
Subject(s) - salinomycin , neuroblastoma , cancer research , paclitaxel , cancer stem cell , stem cell , cancer , medicine , pharmacology , biology , cell culture , biochemistry , microbiology and biotechnology , genetics , antibiotics
Salinomycin, a widely used anti‐coccidial agent, was recently identified from a library of 16,000 natural and commercial chemical compounds based on its highly selective inhibitory effect on breast cancer stem cells (CSCs), with more than 100‐fold greater potency than paclitaxel. Salinomycin also exhibits cytotoxic effects on other types of cancer cells and CSCs and overcomes drug resistance. However, the exact mechanism of salinomycin, especially its direct binding target(s), and its effects on Neuroblastoma (NB) are yet not known. NB is a common solid tumor and a leading cause of mortality in children. Currently, 35% of patients with NB remain incurable. In addition, the majority survivors of NB suffer from long‐term side effects of current therapies and are at risk for disease relapse or getting a second, different cancer. More effective therapies are pressingly needed. Since the existence of CSCs in human NB cell lines and NB tumors has been well documented, and has been closely associated with chemoresistance or tumor relapse, therapeutic targeting of NB CSCs may be a critical novel approach for NB therapy. Aiming to improve NB therapy, we examined the efficacy and mechanism of salinomycin in human NB cells. Our study showed that salinomycin markedly inhibits NB cell proliferation and tumorsphere formation. Treatment of salinomycin induced G2 cell cycle arrest with an up‐regulation of Cyclin A and a down‐regulation of p21 protein levels. We further identified TIF1β and NCL as novel direct binding targets of salinomycin by using comprehensive methods, including chemical proteomics and functional genomics. Furthermore, by analyzing tumor samples from a cohort of 88 NB patients, we found that the elevated level of either TIF1β or NCL is associated with poor prognosis for NB patients. Thus, our results indicate salinomycin is a potential new therapeutic agent and TIF1β and NCL as new therapeutic targets/biomarkers for NB therapy. Grant Funding Source : Supported by ND EPSCoR, NDSU, NIH P20 RR020151, NIGMS (P20 GM103505 and P30 GM103332‐01)