Cover Story Current Issue

Brown adipose tissue (BAT) is a specialized fat tissue that is rich in mitochondria and promotes non-shivering thermogenesis by expressing the uncoupling protein 1 (UCP1). Unlike white adipose tissue, it burns calories to produce heat and therefore plays a key role in energy regulation and controlling metabolic health. Increasing energy expenditure by BAT activation is an intriguing therapeutic approach to combat the overwhelming obesity pandemic, either alone or to complement the current pharmacotherapy that mainly addresses energy intake based on the incretin-mimetic poly-agonist class of drugs. With this in mind it is not surprising that a lot of research was conducted to understand the molecular underpinnings of BAT regulation specifically addressing environmental cues. Cold exposure is the most powerful inducer of BAT activation leading to the upregulation of thermogenic gene program and adrenergic receptor-mediated activation of lipolysis and metabolism. BAT activation also occurs post-prandially, especially after acute overfeeding, to trigger diet-induced thermogenesis. However, this compensatory component of energy-expenditure is impaired during chronic overfeeding, a phenomenon that was termed adaptive thermogenesis, and is believed to further drive weight gain and obesity.

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Current Issue

BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics

Se Seul Im, Jihyeon Seo, Ji Eun You, Hye Won Bang, ... Jaekyoung Son

BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics

 

Objectives

Increased expression of glutaminase (GLS) has been found to correlate with more aggressive disease and poorer prognosis in patients with several types of cancer, including breast, lung, and pancreatic cancer. G9a histone methyltransferase inhibitors may have anticancer activity. The present study assessed whether BIX01294 (BIX), a G9a histone methyltransferase inhibitor, can inhibit glutaminase (GLS) in pancreatic ductal adenocarcinoma (PDAC) cells.

Methods

The effects of BIX on mitochondrial metabolism in PDAC cells were evaluated by targeted liquid chromatography–tandem mass spectrometry (LC-MS/MS) metabolomic analysis. To assess the impact of BIX on glutathione dynamics, real-time changes in glutathione levels were monitored by FreSHtracer-based GSH assays.

Results

BIX significantly inhibited the growth of PDAC cells, both in vitro and in vivo, and robustly induced apoptotic cell death. BIX significantly increased the cellular NADP+/NADPH ratio and decreased the ratio of reduced-to-oxidized glutathione (GSH:GSSG). In addition, BIX decreased GSH levels and increased ROS levels. N-acetyl-l-cysteine (NAC) supplementation dramatically rescued PDAC cells from BIX-induced apoptosis. Furthermore, BIX inhibited the transcription of GLS by inhibiting Jumonji-domain histone demethylases but not G9a histone methyltransferase. One Jumonji-domain histone demethylase, KDM6B, epigenetically regulated GLS expression by binding to the GLS gene promoter.

Conclusions

Collectively, these findings suggest that BIX could be a potent therapeutic agent in patients with PDAC through its inhibition of GLS-mediated cellular redox balance.

 

 

Articles in Press

BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics

Se Seul Im, Jihyeon Seo, Ji Eun You, Hye Won Bang, ... Jaekyoung Son

BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics

 

Objectives

Increased expression of glutaminase (GLS) has been found to correlate with more aggressive disease and poorer prognosis in patients with several types of cancer, including breast, lung, and pancreatic cancer. G9a histone methyltransferase inhibitors may have anticancer activity. The present study assessed whether BIX01294 (BIX), a G9a histone methyltransferase inhibitor, can inhibit glutaminase (GLS) in pancreatic ductal adenocarcinoma (PDAC) cells.

Methods

The effects of BIX on mitochondrial metabolism in PDAC cells were evaluated by targeted liquid chromatography–tandem mass spectrometry (LC-MS/MS) metabolomic analysis. To assess the impact of BIX on glutathione dynamics, real-time changes in glutathione levels were monitored by FreSHtracer-based GSH assays.

Results

BIX significantly inhibited the growth of PDAC cells, both in vitro and in vivo, and robustly induced apoptotic cell death. BIX significantly increased the cellular NADP+/NADPH ratio and decreased the ratio of reduced-to-oxidized glutathione (GSH:GSSG). In addition, BIX decreased GSH levels and increased ROS levels. N-acetyl-l-cysteine (NAC) supplementation dramatically rescued PDAC cells from BIX-induced apoptosis. Furthermore, BIX inhibited the transcription of GLS by inhibiting Jumonji-domain histone demethylases but not G9a histone methyltransferase. One Jumonji-domain histone demethylase, KDM6B, epigenetically regulated GLS expression by binding to the GLS gene promoter.

Conclusions

Collectively, these findings suggest that BIX could be a potent therapeutic agent in patients with PDAC through its inhibition of GLS-mediated cellular redox balance.

 

 

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13th
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