UC Irvine

Abstract

OBJECTIVES

Magmas (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a nuclear gene that encodes for the mitochondrial import inner membrane translocase subunit Tim16. Magmas is highly conserved and ubiquitously expressed in all mammalian cells, and is essential for cell viability. Its expression levels are increased in a significant proportion of human prostate cancers, independently of mitochondria content. In addition, Magmas mRNA is over expressed in two ACTH-secreting pituitary adenoma cell lines as compared to normal pituitary in mouse, as well as in 47 out of 64 pituitary adenomas compared to normal pituitary in human. Moreover, Magmas silencing sensitizes to pro-apoptotic stimuli and induces a G0/G1 accumulation. Based on the above findings, we believed that inhibition of Magmas by small molecule inhibitors could be beneficial for glioma treatment.

METHODS

In this study, we tested the capability of a Magmas inhibitor-BT#9 to cross the blood brain barrier in mice. The anti-tumor effect of BT#9 was investigated using glioma cell lines.

RESULTS

Our in vivo results showed that while the plasma level of BT#9 reaches a Cmax within 5 minutes and is obviously eliminated by 720 minutes, brain levels of BT#9 increase over the first 240 minutes after IV exposure and then slowly decrease, indicating that BT#9 may cross the blood brain barrier. In vitro study using glioma cell lines revealed that Magmas inhibition by BT#9 significantly decreased cell proliferation, induced apoptosis along with vacuole formation, blocked migration and invasion. Since Magmas is a ROS regulator, BT#9 treatment resulted in a decrease in respiratory function of glioma cells.

DISCUSSION

This is the first study about the role of Magmas in glioma. Our findings suggest that Magmas plays a key role in glioma cell survival and targeting Magmas by Magmas inhibitor has the potential to become an therapeutic strategy in gliomas.