A cell-penetrating ARF peptide inhibitor of FoxM1 in mouse hepatocellular carcinoma treatment

We previously developed Tg mice in which the Rosa26 promoter was used to drive ubiquitous expression of the human forkhead box M1b cDNA, and increased FoxM1b levels stimulated proliferation of pulmonary cells in response to lung injury and stimulated development and progression of prostate cancers in both TRAMP/Rosa26-FoxM1b and LADY/Rosa26-FoxM1b double-Tg mice

Galina A. Gusarova; I-Ching Wang; Michael L. Major; Vladimir V. Kalinichenko; Timothy Ackerson; Vladimir Petrovic; Robert H. Costa

2006

Scholarcy highlights

  • Human hepatocellular carcinoma is the fifth most common cancer, yet it is among the most lethal cancers worldwide because late detection and high frequency of tumor recurrence render current hepatocellular carcinomas therapy ineffective
  • We show that administering the WT ARF26–44 peptide to mice following DEN/PB exposure is an effective treatment to diminish forkhead box m1 function in vivo, causing selective HCC apoptosis and reduced proliferation and angiogenesis in HCC regions
  • We showed that WT ARF26–44 peptide treatment of these Arf–/– Rosa26-forkhead box M1b Tg mice efficiently diminished HCC proliferation and selectively induced apoptosis of the HCC region
  • We demonstrated that FoxM1 is required for proliferation of mouse liver cancer cells during tumor progression
  • To pharmacologically reduce in vivo activity of FoxM1 in HCC, mice were subjected to daily injections with a cell-penetrating ARF26–44 peptide inhibitor of FoxM1 function
  • HepG2 cells treated with WT ARF26–44 peptide exhibited dent on FoxM1b transcription factor, we crossed Rosa26-FoxM1b a less severe reduction in levels of survivin, polo-like kinase 1, and Tg mice, which ubiquitously expressed the human FoxM1b cDNA
  • Our results suggest that WT ARF26–44 peptide treatment of cancer cells results in partial inhibition of Foxm1 activity, leading to mitotic catastrophe and apoptosis caused by reducing expression of the mitotic regulators PLK1, aurora B kinase, and survivin proteins to levels that are insufficient for proper mitotic progression
  • Consistent with the specificity of our WT alternative reading frame peptide treatment of mice, we found no changes in liver tumor expression of Mdm2, p53, or NPM/B23 proteins in vivo, and apoptosis was independent of increased expression of PUMA, a p53 target gene required for mediating apoptosis

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