Gene therapy of pancreatic cancer targeting the K-Ras oncogene

V. Lisiansky, I. Naumov, S. Shapira, D. Kazanov, A. Starr, N. Arber*, S. Kraus

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Ras mutations are present in ∼95% of pancreatic cancer (PC) cases leading to increased proliferation and apoptosis resistance. The aim of this study is to selectively kill Ras-transformed cells by overexpressing the pro-apoptotic protein, p53 upregulated modulator of apoptosis (PUMA) under a Ras-responsive promoter. Colo357, Panc1 and MiaPaca, PC cell lines harboring K-Ras mutations, normal rat IEC18 enterocytes, and their K-Ras transformed R1 counterparts, were tested. We constructed adenoviral vectors containing the PUMA gene downstream to: (1) Four or five repetitive Ras-responsive elements (Ad-PY4/PY5-PUMA) and (2) a negative control (Ad-SV40-PUMA). Cell viability was estimated by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and apoptosis was evaluated by FACS. In vivo potency of the adenoviruses was evaluated in athymic nude mice. Infection with Ad-PY4/PY5-PUMA markedly inhibited cell growth (∼40-50%), and apoptosis was detected in all cells with high Ras activity, whereas IEC18 cells remained unaffected. The control vector, Ad-SV40-PUMA, did not induce any cell death. Selective and high expression of PUMA was detected in Ad-PY4-PUMA-infected cells. In vivo, Ad-PY4-PUMA inhibited by ∼35% the growth of established tumors compared with the Ad-SV40-PUMA. Selective overexpression of PUMA efficiently inhibits the growth of Ras-transformed cells while sparing the normal ones. This treatment modality may become a useful, effective and safe approach to selectively target Ras-mutated tumor cells.

Original languageEnglish
Pages (from-to)862-869
Number of pages8
JournalCancer Gene Therapy
Issue number12
StatePublished - Dec 2012


  • K-Ras
  • PUMA
  • adenovirus
  • gene therapy
  • pancreatic cancer (PC)


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