The Role of ATF3, a New p53 Regulator, in Prostate Carcinogenesis

PUBLIC ABSTRACT

Prostate cancer is the most commonly diagnosed cancer and the second leading cause of male cancer death in the United States. This disease is characterized by its strong association with aging, which is accompanied by an increased of oxidative stress that can leads to DNA damage, mutations and eventually the occurrence of a cancer. The tumor suppressor p53 plays a key role in preventing the accumulation of gene mutations by either eliminating damaged cells or allowing for damage repair thereby suppressing the occurrence of a cancer. Thus, loss of p53 function is recognized as a driving force for prostate carcinogenesis. However, the p53 gene is mutated in less than 15% of prostate cancers, suggesting that additional mechanisms are adapted by prostate cancer cells to evade p53 surveillance. For example, downregulation of a p53 regulatory protein can inactive the tumor suppressor leading to carcinogenesis. Therefore, identifying p53 regulatory proteins and further elucidating their roles in prostate carcinogenesis will provide the grounds for developing new strategies targeting these proteins via prophylactic therapy to significantly reduce the incidence of prostate cancer.

This proposal addresses this need by investigating the role of activating transcription factor 3 (ATF3) in prostate carcinogenesis. ATF3 is one of a few proteins that can be induced by a large variety of oxidative stresses. We recently found that this protein is a novel regulator for p53. Through protein-protein interaction, ATF3 can activate p53 and promote its tumor suppression function. Moreover, ATF3 can promote prostate cancer cell death, and its expression is often diminished in prostate cancers. Therefore, we hypothesize that downregulation of ATF3 expression contributes to the occurrence and progression of prostate cancer.

We will test this hypothesis via two specific aims. The first specific aim will determine whether loss of ATF3 gene in mice leads to prostatic lesions, or confers susceptibility to carcinogenesis induced by carcinogens (sex hormones) or a genetic defect (Pten deficiency). This aim will be achieved through a genetic approach, i.e., using genetically-engineered mice. Thus, we will breed mice carrying deleted ATF3 gene or ATF3/Pten double deletions, and examine the mouse prostates to determine the presence of prostatic lesions or carcinomas. The second aim is to determine the effects of ATF3 on the survival of prostate cells. We will suppress ATF3 expression in prostate cancer cells using an innovative approach called RNAi, which allows for expression of a small RNA molecule to break down ATF3 mRNA. These cells will be treated with DNA-damaging agents, and the genes responsible for cell death will be identified. We will also examine the interaction between ATF3 and Par-4 and determine whether ATF3 regulates the survival of prostate cancer cells via the latter protein. Par-4 is known to promote cell death in prostate cancer. Finally, we will determine whether prostate cell death triggered by androgen ablation, which is a conventional therapy for prostate cancer but often fails to cure advanced prostate cancer, will be protected by ATF3 loss using ATF3-deleted mice.

The achievement of this proposed research will reveal the biological significance of a p53 regulatory protein in prostate carcinogenesis, and thus enables us to develop ATF3 as a new preventive and/or therapeutic target for prostate cancer. Since ATF3 can mediate a response to aging-related oxidative stress, the results from this innovative research will also advance our understanding of the relevance of inadequate oxidative stress response to prostate carcinogenesis. Indeed, this understanding is a prerequisite for seeking a better way to fight against prostate cancer.