TMF/ARA160 downregulates proangiogenic genes and attenuates the progression of PC3 xenografts

Abstract

TMF/ARA160 is a Golgi-associated protein whose level is downregulated in solid tumors. TMF changes its subcellular localization on exposure of cells to stress cues, thereby, directing proteins, such as the key transcription factor, Stat3, to proteasomal degradation. Here, we show that enforced ectopic expression of HA-TMF in PC3 prostate carcinoma cells, which do not express Stat3, significantly attenuated the development and growth of xenograft tumors elicited by these cells in athymic mice. Immunohistochemical analysis revealed impaired angiogenesis and accelerated onset of apoptosis in the HA-TMF-expressing tumors. RNA expression profiling revealed the downregulation of several proangiogenic genes in HA-TMF-expressing xenografts. Among these were the interleukin-8 and interleukin-1beta genes, whose expression is controlled by nuclear factor-kB. The level of the nuclear factor-kB component, p65/RelA, was decreased in HA-TMF-expressing xenografts, and TMF was found to direct the ubiquitination and proteasomal degradation of p65/RelA in metabolically stressed PC3 clones. Taken together, our findings indicate that TMF/ARA160 is a regulator of key transcription factors under metabolic constraints, thereby affecting angiogenesis and progression of solid tumors, which are subjected to metabolic stress.