| First Author | Wang L | Year | 2015 |
| Journal | Cancer Biol Ther | Volume | 16 |
| Issue | 3 | Pages | 383-91 |
| PubMed ID | 25695667 | Mgi Jnum | J:279692 |
| Mgi Id | MGI:6363893 | Doi | 10.1080/15384047.2014.1002331 |
| Citation | Wang L, et al. (2015) Heterozygous deletion of ATG5 in Apc(Min/+) mice promotes intestinal adenoma growth and enhances the antitumor efficacy of interferon-gamma. Cancer Biol Ther 16(3):383-91 |
| abstractText | Autophagy related gene 5 (ATG5) was lost in 23% of the patients with colorectal cancer (CRC) and the role of loss of ATG5 in the pathogenesis of CRC remains unclear. Knockdown of ATG5 in cancer cells enhances the antitumor efficacy of lots of chemotherapeutic agents. However, there is still no animal model to validate these in vitro observations in vivo. In this study, we found that heterozygous deletion of ATG5 in Apc(Min/+) mice increased the number and size of adenomas as compared with those in Apc(Min/+)ATG5(+/+) mice. To investigate whether ATG5 deficiency could sensitize tumors to chemotherapies, we compared the antitumor effects of Interferon-gamma (IFN-gamma) between Apc(Min/+)ATG5(+/+) and Apc(Min/+)ATG5(+/-) mice, as IFN-gamma is a potential tumor suppressor for CRC and has been used clinically as an efficient adjuvant to chemotherapy of cancer. We revealed that heterozygous deletion of ATG5 significantly enhanced the antitumor efficacy of IFN-gamma. Early treatment of Apc(Min/+)ATG5(+/-) mice with IFN-gamma decreased tumor incidence rate to 16.7% and reduced the number of adenomas by 95.5% and late treatment led to regression of tumor. Moreover, IFN-gamma treatment did not cause any evident toxic reaction. Mechanistic analysis revealed that heterozygous deletion of ATG5 activated EGFR/ERK1/2 and Wnt/beta-catenin pathways in adenomas of Apc(Min/+) mice and enhanced the effects of IFN-gamma-dependent inhibition of these 2 pathways. Our results demonstrate that ATG5 plays important roles in intestinal tumor growth and combination of IFN-gamma and ATG5 deficiency or ATG5-targeted inhibition is a promising strategy for prevention and treatment of CRC. |
