Abstract 4369: Compound 1, a quinoxaline-based small molecule, regulates the cancer cell proliferantion by the down-regulation of maternal embryonic leucine zipper kinase gene expression in brain tumor cells.

Abstract

Abstract Maternal embryonic leucine zipper kinase (MELK), a member of the snf1/AMPK family of serine-threonine kinase, was indicated in stem cell renewal, cell cycle progression. Recently, several groups reported that MELK expression level is highly correlated with malignancy of a variety of tumors and its expression in the cancer cells is a negative factor of radiotherapy in cancer patients. Therefore, MELK can be a good target for cancer drug development. Previously, we tested the neuronal cell differentiation by the compound-1, a quinoxaline-based small molecule, with rat mesenchymal stem cells, and we found that the gene expression level of MELK is dramatically decreased in the differentiated cells in comparison with the parental stem cells. Based on this phenomenon, we checked the MELK gene expression in the several central nerve system cancer cell lines such as U87MG, XL498 and SNB19, and examined the change of the gene expression level by treatment of compound 1. All the cancer cells tested in this study expressed the MELK gene and its expression level is significantly decreased by the treatment of 20 uM compound 1. To confirm the relationship between the MELK gene expression and cell proliferation in brain tumor cells, we transfected the MELK gene to the U87MG cells and tested the cell growth rate in the presence or absence of compound 1 in comparison with parental cells. The cell growth rate of MELK gene-transfected cancer cells increased in comparison with the non-transfected control cells, and its overexpression can recover the down-regulation of the cell proliferation by treatment of compound 1. Meanwhile, the treatment of MELK gene siRNA decreased the cell proliferation rate of the U87MG cells in time dependent manner. In the cell cycle analysis, compound 1 induced both the increase of apoptotic cell rate from less than 5% to 22% and the decrease of G0/G1 phase U87MG cells in comparison with control. Meanwhile, the S and G2/M phase is not changed by the treatment of compound 1 in the U87MG cells. These results support MELK has an effect on regulation of cancer cell proliferation, and it may be a good target for cancer drug development. Citation Format: Sang-Un Choi, Chi Hoon Park, Mansoor M. Ahmed, Stephen Yoo, Shin-Young Park, Kwangrok Kim. Compound 1, a quinoxaline-based small molecule, regulates the cancer cell proliferantion by the down-regulation of maternal embryonic leucine zipper kinase gene expression in brain tumor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4369. doi:10.1158/1538-7445.AM2013-4369