LITAF and TNFSF15, two downstream targets of AMPK, exert inhibitory effects on tumor growth

LPS-induced TNFα factor (LITAF) is a multiple functional molecule whose sequence is identical to small integral membrane protein of the lysosome/late endosome (SIMPLE). 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 tumor necrosis factor superfamily member 15 (TNFSF15) are upregulated by AMPK. The present study further assesses their biological functions. Thus, we show that AICAR, a pharmacological activator of AMPK, increases the abundance of LITAF and TNFSF15 in the LNCaP and C4-2 prostate cancer cells, which is abrogated by shRNA or 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 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, intratumor injection of TNFSF15 significantly reduces the size of tumors and number of blood vessels and induces changes characteristic of tumor cell differentiation. Therefore, our studies for the first time establish the regulatory axis of AMPK-LITAF-TNFSF15. They also suggest that LITAF may function as a tumor suppressor.