Abstract
Maternal embryonic leucine zipper kinase (MELK) is known to modulate intracellular signaling and control cellular processes. However, the role of MELK in oncogenesis is not well defined. In this study, using two microarray datasets of neuroblastoma (NB) patients, we identified that MELK expression is significantly correlated to poor overall survival, unfavorable prognosis, and high-risk status. We found that MELK is a direct transcription target of MYCN and MYC in NB, and MYCN increases MELK expression via direct promoter binding. Interestingly, knockdown of MELK expression significantly reduced the phosphorylation of target protein Retinoblastoma (pRb) and inhibited NB cell growth. Furthermore, pharmacological inhibition of MELK activity by small-molecule inhibitor OTSSP167 significantly inhibited cell proliferation, anchorage-independent colony formation, blocked cell cycle progression, and induced apoptosis in different NB cell lines including a drug-resistant cell line. Additionally, OTSSP167 suppressed NB tumor growth in an orthotopic xenograft mouse model. Overall, our data suggest that MELK is a novel therapeutic target for NB and its inhibitor OTSSP167 is a promising drug for further clinical development.
Highlights
Neuroblastoma (NB) is the most common extracranial neoplasm in children and contributes to about 15% of all pediatric cancer-related deaths (1)
In this study, using two microarray datasets of neuroblastoma (NB) patients, we identified that Maternal embryonic leucine zipper kinase (MELK) expression is significantly correlated to poor overall survival, unfavorable prognosis, and high-risk status
These findings indicate that MELK expression is an important factor in the biology and therapeutic response for high-risk NB
Summary
Neuroblastoma (NB) is the most common extracranial neoplasm in children and contributes to about 15% of all pediatric cancer-related deaths (1). Despite major advances in therapies over the past decade, the overall outcome for high-risk NB patients is still unacceptable [1]. Current therapies include chemotherapy drugs that are highly toxic to healthy cells and have significant long-term side effects. Developing novel targeted therapies for high-risk NB is critical to achieve higher efficacy and to alleviate adverse effects. MYCN amplification is a strong characteristic of highrisk NB patients and serves as a genetic marker of disease [2, 3]. Finding therapeutic strategies to directly target MYCN is a difficult task due to its protein structure. Www.impactjournals.com/oncotarget identifying and characterizing druggable targets in MYCN regulators and transcriptional targets in NB may help us to develop efficient therapeutic strategies
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