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.
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Abbreviations
- AMPK:
-
AMP-activated protein kinase
- AICAR:
-
5-aminoimidazole-4-carboxamide ribonucleoside
- BAEC:
-
bovine aortic endothelial cell
- CMT1C:
-
Charcot–Marie–Tooth type 1C disease, an autosomal genetic disease with demyelinating periphery nervous system
- GAPDH:
-
glyceraldehyde 3-phosphate dehydrogenase
- LKB1:
-
liver kinase B, also named serine/threonine kinase 11 (STK11)
- LITAF:
-
lipopolysaccharide-induced tumor necrosis factor α factor
- LPS:
-
lipopolysaccharide
- SIMPLE:
-
small integral membrane protein of the lysosome/late endosome
- TNFSF15:
-
tumor necrosis factor superfamily member 15
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Acknowledgements
This work is supported by NIH grants (R01 CA118918 to ZL, R01 DE014079 to SA and CA124490 to CC). We thank Dr Zhixiong Xiao (BUMC) for providing p53 shRNA pSuperRetro construct as a generous gift. We are also thankful to Miss Siu Wong for her assistance in animal dissection, to Dr Wen Guo for helping us with confirmatory qPCR analysis and to Dr Mengwei Zang for her advice on statistical analysis.
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Zhou, J., Yang, Z., Tsuji, T. et al. LITAF and TNFSF15, two downstream targets of AMPK, exert inhibitory effects on tumor growth. Oncogene 30, 1892–1900 (2011). https://doi.org/10.1038/onc.2010.575
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DOI: https://doi.org/10.1038/onc.2010.575
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