The Anticancer Agents Chloroquine and Veratrine Induce UBXN2A, a Potential Positive Mediator of p53 Tumor Suppressor

Kaitlin A. Branick


Colorectal cancer is the third leading cause of cancer-related deaths in developed countries, causing over 50,000 deaths annually in the US alone. Promotion of malignancy due to the inactivation of the wild type (normal) p53 tumor suppressor gene (WT-p53) is observed in greater than 50% of colon cancers. The growth arrest of colon cancer cells by the reintroduction of WT-p53 further supports a significant role of p53 in colon tumor suppression. Currently, the mechanisms involved in p53 inactivation and re-activation are poorly understood. One potential mechanism of p53 inactivation is by limiting its localization in the cytoplasm (cytoplasmic sequestration). By keeping p53 out of the nucleus, it fails to execute its anti-cancer functions. One protein that keeps p53 in the cytosol, and thus effectively promotes cancer cell proliferation, is Mortalin-2 (Mot2). We have identified a novel protein, UBXN2A, that causes Mortalin-2 to release p53, resulting in the return of p53 to the nucleus where it can suppress tumor cell growth. In addition, our study identified one FDA-approved drugs (Chloroquine) and a natural plant product (Veratrine), which enhance UBXN2A expression in colon cancer cells. In this project, we tested the hypothesis that enhancing UBXN2A using these identified agents can result the induction of apoptosis in colon cancer cells.