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Novel approach to abuse the hyperactive K-Ras pathway for adenoviral gene therapy of colorectal cancer.

Abstract：

BACKGROUND:Functional activation of oncogenic K-Ras signaling pathway plays an important role in the early events of colorectal carcinogenesis (CRC). K-Ras proto-oncogene is involved in 35-40% of CRC cases. Mutations in the Ras gene trigger the transduction of proliferative and anti-apoptotic signals, even in the absence of extra cellular stimuli. The objective of the current study was to use a gene-targeting approach to kill human CRC cells selectively harboring mutated K-Ras. RESULTS:A recombinant adenovirus that carries a lethal gene, PUMA, under the control of a Ras responsive promoter (Ad-Py4-SV40-PUMA) was used selectively to target CRC cells (HCT116, SW480, DLD1 and RIE-Ras) that possess a hyperactive Ras pathway while using HT29 and RIE cells as a control that harbors wild type Ras and exhibit very low Ras activity. Control vector, without the Ras responsive promoter elements was used to assess the specificity of our "gene therapy" approach. Both adenoviral vectors were assed in vitro and in xenograft model in vivo. Ad-Py4-SV40-PUMA showed high potency to induce ~50% apoptosis in vitro, to abolish completely tumor formation by infecting cells with the Ad-Py4-SV40-PUMA prior xenografting them in nude mice and high ability to suppress by ~35% tumor progression in vivo in already established tumors. CONCLUSIONS:Selective targeting of CRC cells with the activated Ras pathway may be a novel and effective therapy in CRC. The high potency of this adenoviral vector may help to overcome an undetectable micro metastasis that is the major hurdle in challenging with CRC.

journal_name

Exp Cell Res

journal_title

Experimental cell research

authors

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

doi

10.1016/j.yexcr.2011.09.015

subject

Has Abstract

pub_date

2012-01-15 00:00:00

pages

160-8

issue

2

eissn

0014-4827

issn

1090-2422

pii

S0014-4827(11)00391-0

journal_volume

318

pub_type

杂志文章

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