THE DIFFERENTIAL EFFECTS OF ALL-TRANS RETINOIC ACID ON RETINOIC ACID RECEPTOR (RAR)- AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-β/δ (PPARβ/δ)-DEPENDENT SIGNALING IN THE HUMAN NT2/D1 TESTICULAR EMBRYONAL CANCER CELL LINE

Open Access
Author:
Dobrzanski, Tomasz Pawel
Area of Honors:
Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Jeffrey Maurice Peters, Thesis Supervisor
  • Katriona Shea, Honors Advisor
Keywords:
  • testicular cancer
  • embryonal carcinoma
  • all-trans retinoic acid (atRA)
  • Peroxisome proliferator activated receptor-β/δ (PPARβ/δ)
Abstract:
The nuclear hormone receptor peroxisome proliferator-activated receptor-beta/delta (PPARβ/δ) has been shown to promote and inhibit tumorigenesis, suggesting a context-specific role for PPARβ/δ in carcinogenesis. Previous literature suggests that all-trans retinoic acid (atRA) promotes cell proliferation through activation of PPARβ/δ, but more recent literature has been unable to confirm this role for atRA in PPARβ/δ signaling and carcinogenesis. The viability of this hypothesis was tested in the human NT2/D1 testicular cancer cell line by treating cells with atRA and/or PPARβ/δ agonists, and examining the effect on the retinoic acid receptor (RAR) and PPARβ/δ signaling pathways. atRA decreased the intracellular ratio of retinoic acid-shuttling proteins (FABP5:CRABP-II) by increasing levels of CRABP-II, whereas the synthetic PPARβ/δ agonists GW0742 and GW501516 had no effect on the relative expression of FABP5 to CRABP-II. As expected, atRA activated RAR signaling, but had no effect on PPARβ/δ levels, a known PPARβ/δ target gene, or cell proliferation. Interestingly, ligand activation of PPARβ/δ repressed RAR signaling and cell proliferation. Taken together, these data support the hypothesis that atRA is not a PPARβ/δ ligand and that activation of PPARβ/δ signaling inhibits carcinogenesis in testicular cancer.