NAD+ Synthesis, Mono(ADP-Ribosyl)ation, Protein Translation, and Proteostasis in Ovarian Cancer
Abstract
1. Problem to Be Addressed: Ovarian Cancer. Ovarian cancer is a devastating disease that destroys lives and disrupts families. It is the 10th most common cancer among women in the United States, with more than 20,000 women diagnosed with the disease each year. However, sadly, it is the fifth leading cause of cancer mortality in women (~14,000 deaths per year) and the most deadly of all gynecologic cancers, with less than 50% of patients surviving 5 years. Early-stage ovarian cancer is difficult to detect and, as a result, most patients have advanced disease (Stage III-IV) at diagnosis. Despite advances in surgery and chemotherapy for the treatment of advanced ovarian cancers, up to 85% eventually relapse and response to subsequent therapies is short-lived. Clearly, there is a need for major improvements in the diagnosis and treatment of ovarian cancer. 2. Background: PARP Inhibitors – New Drugs to Treat Ovarian Cancer. In 2014, the U.S. Federal Drug Administration (FDA) approved the use of a new class of drugs, called PARP inhibitors, for the treatment of ovarian cancers that exhibit genetics lesions (mutations) in genes called BRCA1 and BRCA2, which are needed for DNA repair and maintaining the integrity of the genome. There are now four FDA-approved PARP inhibitors that are used for BRCA1- and BRCA2-mutated ovarian cancers. These drugs act by inhibiting the activity of poly(ADP-ribose) polymerase (PARP) enzymes, specifically PARP-1 and PARP-2, which localize to the nuclei of cells where the genome is stored. PARP-1 and PARP-2 also play key roles in DNA repair and maintaining the integrity of the genome. The extensive DNA damage caused by the PARP inhibitors in combination with BRCA1/2 mutations kills the ovarian cancer cells. PARP-1 and PARP-2 belong to a family of related enzymes comprising 17 members, each with distinct functions in the cell. We have asked whether it would be possible to target other members of the PARP family with new PARP inhibitors to treat ovarian cancers. The research described in our proposal will address this question. PARPs, NAD+, and ADP-Ribosylation. Members of the PARP family are enzymes that transfer and chemically link a small molecule called ADP-ribose (ADPR) onto proteins through a process called ADP-ribosylation (ADPRylation). The ADPR is derived from a larger molecule, NAD+, which is consumed by PARP enzymes to obtain ADPR. Thus, re-synthesis of NAD+ in the cells is essential to support the activity of PARPs. PARP-1 and PARP-2 transfer chains (or polymers) of ADPR, but most family members only transfer single ADPR units through a process called monoADP-ribosylation (MARylation). The biological roles of these “mono” enzymes and MARylation are poorly studied, and there are currently no FDA-approved drugs to inhibit them. We are attempting to change that through our research. Our hope is that our research will further the development of new PARP inhibitor drugs that can be used to treat a broader group of ovarian cancer patients. Ribosomes, Protein Translation, and Cancer. Ribosomes are the machines in cells that make proteins from the genetic information stored in the nucleus. Fast-dividing cells, such as cancer cells, require high levels of protein synthesis to support cell growth. However, when the levels of protein synthesis are too high, the proteins cannot be folded correctly, resulting in the accumulation of toxic protein aggregates. Hence, cells must maintain a balance between protein synthesis and protein removal to maintain optimum protein levels. Ribosomes are a hub for this regulation. Recent studies from our laboratory and others have found that ribosomes are MARylated in mammalian cells, including in ovarian cancer cells. Our preliminary data suggest an intriguing link between ribosomal MARylation and ribosome function in growth regulation in ovarian cancers. 3. Preliminary Results and Research Plan: Identification of a New Dr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110685
Entities
People
- William Kraus
Organizations
- United States Army
- University of Texas Southwestern Medical Center