NYMC Faculty Publications
LITAF and TNFSF15, Two Downstream Targets of AMPK, Exert Inhibitory Effects on Tumor Growth
Author Type(s)
Faculty
Additional Author Affiliation
Touro College of Dental Medicine at NYMC
DOI
10.1038/onc.2010.575
Journal Title
Oncogene
First Page
1892
Last Page
1900
Document Type
Article
Publication Date
4-21-2011
Department
Pharmacology
Abstract
Lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) α factor (LITAF) is a multiple functional molecule whose sequence is identical to the small integral membrane protein of the lysosome/late endosome. LITAF was initially identified as a transcription factor that activates transcription of proinflammatory cytokine in macrophages in response to LPS. Mutations of the LITAF gene are associated with a genetic disease, called Charcot-Marie-Tooth syndrome. Recently, we have reported that mRNA levels of LITAF and TNF superfamily member 15 (TNFSF15) are upregulated by 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK). The present study further assesses their biological functions. Thus, we show that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a pharmacological activator of AMPK, increases the abundance of LITAF and TNFSF15 in LNCaP and C4-2 prostate cancer cells, which is abrogated by small hairpin RNA (shRNA) or the dominant-negative mutant of AMPK α1 subunit. Our data further demonstrate that AMPK activation upregulates the transcription of LITAF. Intriguingly, silencing LITAF by shRNA enhances proliferation, anchorage-independent growth of these cancer cells and tumor growth in the xenograft model. In addition, our study reveals that LITAF mediates the effect of AMPK by binding to a specific sequence in the promoter region. Furthermore, we show that TNFSF15 remarkably inhibits the growth of prostate cancer cells and bovine aortic endothelial cells in vitro, with a more potent effect toward the latter. In conjuncture, intratumoral injection of TNFSF15 significantly reduces the size of tumors and number of blood vessels and induces changes that are characteristic of tumor cell differentiation. Therefore, our studies for the first time establish the regulatory axis of AMPK-LITAF-TNFSF15 and also suggest that LITAF may function as a tumor suppressor.
Recommended Citation
Zhou, J., Yang, Z., Tsuji, T., Gong, J., Xie, J., Chen, C., Li, W., Amar, S., & Luo, Z. (2011). LITAF and TNFSF15, Two Downstream Targets of AMPK, Exert Inhibitory Effects on Tumor Growth. Oncogene, 30 (16), 1892-1900. https://doi.org/10.1038/onc.2010.575
