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      SREBP Inhibitor, PF429242, Suppresses Proliferation of Prostate Cancer Cell Lines

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      Revised Thesis 3-CT revised Jan2016 (3).pdf (893.9Kb)
      Date
      2016-01-21
      Author
      khalaj, Sara
      Type
      Thesis
      Degree Level
      Masters
      Metadata
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      Abstract
      According to experimental and epidemiological evidence cholesterol may play an important role in development and promotion of prostate cancer. Sterol regulatory element-binding proteins (SREBP; SREBP-1 and SREBP-2) are key transcription factors controlling lipogenesis via the regulation of genes related to biosynthesis of fatty acid and cholesterol. Since the over-expression of SREBPs has been associated with aggressive features of human prostate cancer, the goal of present study was to evaluate the anti tumor activity of a novel SREBP inhibitor, PF429242 for the first time. PF429242 suppressed cell proliferation in both androgen sensitive LNCaP and androgen insensitive C4-2 prostate cancer cells. The inhibitory effect of PF429242 (mean±SEM) was comparable to the similar compound, Fatostatin (mean±SEM), which was studied earlier on prostate cancer. The observed IC50 was closely similar between the two cell lines (IC50 9.6µM in LNCaP, IC50 9.8µM in C4-2). However, when the inhibitory effects of PF429242 compared to Paclitaxel which is the currently the rational drug for clinical management of prostate cancer, a significant difference was observed. Further, PF429242 suppressed n-SREBP activation followed by decreased FAS expression in both androgen sensitive and insensitive cells. Also, caspase3 activation increased in both cell lines following treatment. The pharmacological effects of PF429242 are attributed to the inhibition S1P in SREBP pathway. The findings from the present study provide the impetus to examine whether S1P inhibitor, PF429242, would serve as a potential additive agent in suppressing the early stages of hormone dependent/Independent prostate cancer.
      Degree
      Master of Science (M.Sc.)
      Department
      Pharmacology
      Program
      Pharmacology
      Copyright Date
      December 2015
      URI
      http://hdl.handle.net/10388/12606
      Subject
      SREBP, FAS, Caspase3, S1P, LNCaP,C4-2, PF429242
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