Arginine modulates the mitochondrial function via mTOR-TEAD4 axis in prostate cancer cells

Identification: Chen, Chia-Lin


Description

 

Arginine modulates the mitochondrial function via mTOR-TEAD4 axis in prostate cancer cells
 
Chia-Lin Chen1, Hsing-Jien Kung1*
1Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, 350, Taiwan
*Corresponding Author
      
Prostate cancer, a disease of aged population, has risen sharply in incidence in Taiwan, and now ranks no. 5 as the leading cause of cancers in Taiwan men.  Prostate cancer is a hormonally regulated malignancy and androgen receptor plays an important role in disease progression. One of the most troubling aspects of prostate cancer progression is the cancer cell transformation from androgen-dependent to independent state (also known as castration-resistant state), which at present defies any effective treatment. Thus, there is an urgent need to identify intervention targets and develop therapeutics to overcome castration-resistance.
Emerging evidence has been shown that various type of cancers, including prostate cancer, are addictive to extracellular arginine supplement due to the loss function of arginine synthesis enzyme, argininosuccinate synthase 1. However, the role of arginine in prostate cancer cells remains unclear. Previously, we show that arginine deprivation induces atypical cellular death, which involves mitochondrial dysfunction, nuclear DNA leakage, and chromatin autophagy1. In addition, our in vivo data indicates that the treatment of arginine deiminase enzyme, can suppress the prostate tumor growth. These data suggest arginine plays an important role in prostate cancer cells, especially in mitochondrial function.
In this study, we elucidate that arginine regulates the expression of mitochondrial oxidative phosphorylation (OXPHOS) pathway as well as mitochondrial respiration activity via mTORC1-TEAD4 axis in prostate cancer cells. Either suppression of mTORC1 activity via arginine deprivation or silencing of TEAD4 expression via shRNA lentivirus infection causes downregulation of OXPHOS gene expression. Moreover, disruption of the mTORC1-TEAD4 axis leads to mitochondrial dysfunction and ROS production. These results suggest that suppression of mTOR-TEAD4 axis would inhibit the cancer cell growth and become a new avenue for cancer therapy.
 
References: Proc Natl Acad Sci U S A. 2014 Sep 30;111(39):14147-52.
 
Funding: MOST 106-2321-B-400 -012 -MY3

 

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