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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
TMF/ARA160 downregulates proangiogenic genes and attenuates the progression of PC3 xenografts
Galya Abrham1, Marina Volpe, Sally Shpungin
1The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
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.
Insights
Tumor protein TMF/ARA160, when expressed ectopically, inhibits prostate cancer growth by impairing angiogenesis and promoting apoptosis. TMF/ARA160 targets nuclear factor-kappaB for degradation, impacting tumor progression under metabolic stress.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Tumor protein TMF/ARA160 is downregulated in solid tumors.
- TMF/ARA160 influences protein degradation pathways, including Stat3, upon cellular stress.
- Prostate carcinoma cells (PC3) typically lack Stat3 expression.
Purpose of the Study:
- To investigate the role of ectopically expressed TMF/ARA160 in prostate cancer xenograft growth.
- To determine the impact of TMF/ARA160 on tumor angiogenesis, apoptosis, and gene expression.
- To elucidate the mechanism by which TMF/ARA160 affects key transcription factors in cancer cells.
Main Methods:
- Enforced ectopic expression of HA-TMF in PC3 prostate carcinoma cells.
- Xenograft tumor implantation in athymic mice.
- Immunohistochemical analysis for angiogenesis and apoptosis.
- RNA expression profiling to identify gene expression changes.
- Western blot analysis to assess protein levels and ubiquitination.
Main Results:
- Ectopic HA-TMF expression significantly attenuated xenograft tumor development and growth.
- HA-TMF-expressing tumors showed impaired angiogenesis and increased apoptosis.
- RNA profiling revealed downregulation of proangiogenic genes, including IL-8 and IL-1beta.
- TMF/ARA160 mediated the ubiquitination and proteasomal degradation of p65/RelA (NF-kB component).
Conclusions:
- TMF/ARA160 acts as a tumor suppressor in prostate cancer.
- TMF/ARA160 regulates angiogenesis and apoptosis through modulation of transcription factors like NF-kB.
- TMF/ARA160's function is critical in managing tumor progression under metabolic stress conditions.
