Androgenic Regulation of White Adipose Tissue-Prostate Cancer Interactions
Final rept. 1 May 2010-31 May 2015
M D ANDERSON CANCER CENTER HOUSTON TX
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Glipr1 mouseGLIPR1 human is a direct p53 target gene that encodes a member of the pathogenesis-related protein family. This 28-kDa protein has a putative signal peptide sequence and a transmembrane domain suggesting extracellular functional activity. We have shown that Glipr1GLIPR1 functions as a tumor suppressor through proapoptotic signaling in prostate cancer and potentially other malignancies. We recently discovered that recombinant Glipr1GLIPR1 protein rGlipr1rGLIPR1 treatment results in growth arrestapoptotic cell death in multiple prostate cancer cell lines in vitro. Further preclinical studies using PC-3 xenograft models demonstrated that rGLIPR1 suppressed PC-3 tumor growth when administered intratumorally or intraperitoneally. Although the direct growth suppressorpro-apoptotic activities of Glipr1GLIPR1 are now established, the physiological functions of GLIPR1 remain largely unknown. To further study Glipr1GLIPR1 protein functions we generated mice harboring a targeted inactivation of the Glipr1 gene. We discovered that the wet weight of Glipr1 KO male white adipose tissue WAT was increased compare to the Glipr male littermates Glipr1 WT. Based on these initial observations we pursued additional experiments. Overall, our preliminary data indicate that, in addition to direct growth suppressorpro-apoptotic activities of Glipr1GLIPR1 in prostate cancer cells, testosterone stimulated, prostate derived serum Glipr1GLIPR1 is a hormone that can inhibit WAT function, including suppression of leptin secretion. Increased serum leptin levels may promote prostate cancer progression. We propose to study gene expression in the WAT and prostate tissues of Glipr1 WT and Glipr1 KO animals to characterize the genetic pathways that are affected by the presence or absence of Glipr1.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research