Anti-Tumor Effects of Sodium Meta-Arsenite in Glioblastoma Cells with Higher Akt Activities.

Eun Jeong Lee,Jee Young Sung,Jongsun Park,Jong Bae Park,Yong-Nyun Kim,Kyung Hee Koo,Chang Hoon Lee,Dae Hong Kim,Jaegal Shim

doi:10.3390/ijms21238982

Eun Jeong Lee, Jee Young Sung + Show 7 more

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https://doi.org/10.3390/ijms21238982

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Abstract

Glioblastoma is a type of aggressive brain tumor that grows very fast and evades surrounding normal brain, lead to treatment failure. Glioblastomas are associated with Akt activation due to somatic alterations in PI3 kinase/Akt pathway and/or PTEN tumor suppressor. Sodium meta-arsenite, KML001 is an orally bioavailable, water-soluble, and trivalent arsenical and it shows antitumoral effects in several solid tumor cells via inhibiting oncogenic signaling, including Akt and MAPK. Here, we evaluated the effect of sodium meta-arsenite, KML001, on the growth of human glioblastoma cell lines with different PTEN expression status and Akt activation, including PTEN-deficient cells (U87-MG and U251) and PTEN-positive cells (LN229). The growth-inhibitory effect of KML001 was stronger in U87-MG and U251 cells, which exhibited higher Akt activity than LN229 cells. KML001 deactivated Akt and decreased its protein levels via proteasomal degradation in U87-MG cells. KML001 upregulated mutant PTEN levels via inhibition of its proteasomal degradation. KML001 inhibited cell growth more effectively in active Akt-overexpressing LN229 cells than in mock-expressing LN229 cells. Consistent with these results, KML001 sensitized PTEN-deficient cells more strongly to growth inhibition than it did PTEN-positive cells in prostate and breast cancer cell lines. Finally, we illustrated in vivo anti-tumor effects of KML001 using an intracranial xenograft mouse model. These results suggest that KML001 could be an effective chemotherapeutic drug for the treatment of glioblastoma cancer patients with higher Akt activity and PTEN loss.

Highlights

Glioblastomas are intra-axial tumors that originate from neuroglial cells of the central nervous system (CNS) [1,2]
Because KML001 induces Akt inactivation and phosphatase and tensin homolog (PTEN) activation [19] and because Akt activation with PTEN mutation is associated with glioblastoma, in this study, we evaluated the anti-tumor effects of KML001 using PTEN-negative human glioblastoma U87-MG cells in vitro and in vivo, and investigated the possible mechanisms involved in this process
U87-MG cells are known to contain in-frame deletion of Exon 3 within the tensin region [21]. Comparable levels of this mutation were expressed at the transcriptional level, the mutant PTEN protein was not detected by immunoblotting in U87-MG cells (Figure 1B left panel and lower panel)

Summary

Introduction

Glioblastomas are intra-axial tumors that originate from neuroglial cells of the central nervous system (CNS) [1,2]. The current standard treatment strategy for glioblastoma is multimodal, involving maximal surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ) [2]. Recent insights into the biology of glioblastoma, including those from The Cancer Genome Atlas, have revealed important genetic events in human glioblastomas, such as gene amplification, mutation, and deletion [1,5]. The most frequent alterations in gliomas include dysregulation of growth factor signaling via amplification and mutational activation of receptor tyrosine kinase genes such as EGFR. Phosphatidylinositol-3-kinase (PI3K) signaling pathways are activated due to genetic alteration in the phosphatase and tensin homolog (PTEN) tumor suppressor gene on 10q23.3 at the level of loss of heterozygosity, mutation, and methylation in at least 60% of gliomas [6]

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