Induction of the p53 Tumor Suppressor in Cancer Cells through Inhibition of Cap-Dependent Translation

ABSTRACT

The p53 tumor suppressor plays a critical role in protecting normal cells from malignant transformation. Development of small molecules to reactivate p53 in cancer cells has been an area of intense research. We previously identified an internal ribosomal entry site (IRES) within the 5′ untranslated region of p53 mRNA that mediates translation of the p53 mRNA independent of cap-dependent translation. Our results also show that in response to DNA damage, cells switch from cap-dependent translation to cap-independent translation of p53 mRNA. In the present study, we discovered a specific inhibitor of cap-dependent translation, 4EGI-1, that is capable of inducing the accumulation of p53 in cancer cells retaining wild-type p53. Our results show that 4EGI-1 causes an increase in p53 IRES activity, leading to increased translation of p53 mRNA. We also observed that 4EGI-1 induces cancer cell apoptosis in a p53-dependent manner. Furthermore, 4EGI-1 induces p53 in cancer cells without causing DNA double-strand breaks. In conclusion, we discovered a mechanistic link between inhibition of cap-dependent translation and enhanced p53 accumulation. This leads to apoptosis of cancer cells without causing collateral damage to normal cells, thus providing a novel and effective therapeutic strategy for cancer.

KEYWORDS:

• 4EGI-1
• p53
• eIF4E
• IRES

ACKNOWLEDGMENTS

We thank Peter Bitterman and Douglas Yee (University of Minnesota) for helpful comments on the results presented in the manuscript.

Funding for this research was provided by two research grants (1RO3 CA177954 and 1R01 CA157012) from the National Cancer Institute of the National Institutes of Health, an institutional research grant (118198-IRG-58-001-52-IRG99) from the American Cancer Society, a pilot grant from the Prostate Cancer Translational Working group of UMN, and the Hormel Foundation.