Mol Cancer Res. 2005 Dec;3(12):685-91.
Interleukin-12 up-regulates Fas expression in human
osteosarcoma and Ewing's sarcoma cells by enhancing its promoter
activity.
Zhou Z, Lafleur EA, Koshkina NV, Worth LL, Lester MS, Kleinerman ES.
Division of Pediatrics, The University of Texas M.D. Anderson Cancer
Center, Houston, TX 77030, USA.
Interleukin-12 (IL-12) has shown significant antitumor activity in
several preclinical animal tumor models. Our previous studies showed
that IL-12 inhibited tumor growth in human osteosarcoma and Ewing's
sarcoma animal model. Decreased Fas expression in osteosarcoma
increased the lung metastatic potential. In this study, we further
examined the mechanism of IL-12 antitumor activity and showed that
IL-12 significantly increased Fas expression in both human osteosarcoma
cells LM7 and Ewing's sarcoma cells TC71. Up-regulation of Fas
expression increased their sensitivity to Fas-induced cell apoptosis.
Constructs of the Fas promoter linked to a luciferase reporter gene
were used to determine the promoter activity. IL-12 increased Fas
promoter activity 4.2- and 4.9-fold in TC71 and LM7 cells,
respectively. Time course studies have shown that recombinant IL-12
stimulated Fas promoter activity at 2 hours, reached the peak level at
4 hours, and then declined at 24 hours. To investigate whether IL-12
specifically enhanced Fas promoter activity, we determined whether
another gene (E1A) was able to stimulate Fas promoter activity. We also
evaluated effect of IL-12 on the topoisomerase IIalpha promoter. The
results indicated that E1A but not IL-12 stimulated topoisomerase
IIalpha promoter activity. E1A failed to increase Fas promoter
activity. We also found that kappaB-Sp1 element at position -295 to
-286 in Fas promoter was essential for IL-12-induced activation, and
nuclear factor-kappaB transcription factor was activated after IL-12
treatment in TC71 cells. These results indicate that IL-12 up-regulates
Fas expression in human osteosarcoma and Ewing's sarcoma by enhancing
Fas promoter activity. Understanding this mechanism may lead to new
therapeutic approaches for the treatment of sarcoma involving the use
of IL-12.
PMID: 16380506 [PubMed – indexed for MEDLINE]