The p53 tumor suppressor protein protects cells against malignant transformation through induction of either cell cycle arrest or apoptosis. Since p53 is the most commonly mutated gene in cancer, the vast majority of research examining the link between p53 and cancer has been aimed at characterizing the genetic mutations that alter the p53 protein and lead to the loss of its transcriptional activity in cancer cells. However, mutations in the p53 coding region occur at a significantly lower rate in breast (20%) and prostate (18%) cancers than in other solid tumors, such as lung cancer (70%). Our results provide convincing evidence that defective p53 synthesis following DNA damage can lead to malignant transformation of breast tumor cells even though they retain the wild-type p53 coding region. Since defective p53 synthesis may be one of the key underlying mechanisms for tumorigenesis in these cancer cells, chemical compounds that can restore p53's tumor suppressive function in these cells may become highly effective preventive or therapeutic agents against cancer. Cap-dependent initiation of protein translation is used by the majority of eukaryotic mRNAs, since most of them have an N7-methylguanosine cap structure at their 5'-ends. eIF-4E is a translation initiation protein that binds to the cap structure and drives cap-dependent translation. It is known that the activity of eIF- 4E is elevated in cancer cells and its overexpression and hyperactivation cause malignant transformation and metastasis in various types of cancers, including breast and prostate cancer. Recent results have shown that inhibition of eIF-4E induces apoptosis in cancer cells. However, the underlying mechanism for induction of apoptosis by blocking cap-dependent translation is unclear. We discovered that an internal ribosome entry site (IRES) sequence is present at the 5'-untranslated region (UTR) of p53 mRNA. This is an alternate form of cap-dependent translation in which ribosomal subunits are recruited to an IRES sequence by a subset of initiation factors without the participation of eIF-4E. Multiple lines of recent evidence have revealed a new mechanism by which cap-dependent translation switches to cap-independent translation, including IRES- mediated p53 synthesis, following cyto- or genotoxic stress. Since cap-dependent translation is usually compromised by stressful conditions such as DNA damage, we hypothesize that treatment of cancer cells with inhibitors of cap-dependent translation may cause a similar transition from cap-dependent translation to IRES-mediated translation of p53, leading to apoptosis. The goal of this project is to test this hypothesis by treating cancer cells with several newly discovered cap-dependent translation inhibitors and to examine whether these inhibitors can restore p53's tumor suppressive function in non-p53 responsive cancer cells. Findings from this project will provide new insights into the functional link between suppression of cap- dependent translation and p53 induction and may lead to new therapeutic agents against cancer.

Public Health Relevance

In this project, we will determine if treatment of breast cancer cells with several newly discovered inhibitors of cap-dependent translation causes a transition from cap-dependent translation to IRES-mediated translation of the p53 tumor suppressor, leading to apoptosis. Results obtained from this project may lead to new therapeutic strategies and agents against cancer with defective response to p53.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA177954-01
Application #
8565086
Study Section
Special Emphasis Panel (ZCA1-GRB-I (J1))
Program Officer
Strasburger, Jennifer
Project Start
2013-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$76,250
Indirect Cost
$26,250
Name
University of Minnesota Twin Cities
Department
None
Type
Organized Research Units
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455