RBP-Mediated MLO Formation in Chemoresistance and Cancer Recurrence
Abstract
High-grade serous epithelial ovarian cancer (HGSOC) is the most common, aggressive and lethal form of ovarian cancer. Our research identified that an RNA binding protein, Fragile X Mental Retardation gene 1 (FXR1), is highly expressed in more than 40% of ovarian cancer patients. Notably, FXR1 expression is associated with poor overall survival in ovarian cancer patients. Our data demonstrate that FXR1 is a key regulator of translation blocking (protein synthesis blocking) mechanisms of a set of important tumor suppressors in normal epithelial cells. Protein synthesis is required to be tightly regulated for the synthesis of an accurate amount of proteins for normal cellular functions. Therefore, disruption of normal translation (protein synthesis) by FXR1 leads to a deficiency of several tumor suppressor genes, which in turn causes aggressive cell proliferation, cancer cell invasion, metastasis, and resistance to chemotherapy. Strikingly, our data demonstrated that FXR1 inhibits the protein synthesis of several tumor suppressors such as cyclin-dependent kinase inhibitors CDKN1A, CDKN1B, CDKN2A, and CDKN2B mRNA due to their condensation into membrane-less organelles (MLOs) in normal epithelial cells. Cyclin-dependent kinase inhibitors such as CDKN1A, CDKN1B, CDKN2A and CDKN2B are required to prevent cell cycle progression by normalizing the functions of cyclins in both normal and cancer cells. Therefore, our studies uncovering novel mechanisms that cause translational blockade of tumor suppressors will provide novel therapeutic opportunities to treat ovarian cancer. We found that the MLOs formed by FXR1 protein serve as condensed units of protein-mRNA, complex where tumor suppressor genes are trapped, and their translation (protein synthesis) is inactivated. As a consequence, FXR1 promotes oncogenic transformation of normal cells to tumor cells. Therefore, the main objective of this proposal is to uncover the mechanism of how does FXR1 causes translational blockade of tumor suppressor genes for the survival of tumor cells and resistance to cell death mechanisms. Our preliminary data proved that FXR1 causes the condensation of protein-tumor suppressor mRNAs through liquid-liquid phase separation (LLPS) and MLO formation. We hypothesize that the binding of FXR1 to the key tumor suppressor genes on the AU-Rich element (ARE) leads to the change in the secondary structure of mRNA. We also hypothesize that the binding of FXR1 on AREs causes changes in the secondary structure that will allow the condensation of FXR1-bound tumor suppressor mRNAs and lead to MLO formation. Therefore, the binding of FXR1 to a selective set of mRNAs results in a deficiency in the levels of tumor suppressor proteins in ovarian cancer cells, which causes resistance to chemotherapy and recurrence after therapy. We will test our hypothesis using the following aims: (1) delineate the mechanism of how FXR1 interacts with its target mRNAs for membrane-less organelles formation; (2) determine the mechanism of how FXR1 promotes membrane-less organelles formation; and (3) characterize the effect of FXR1 mediated MLO formation on ovarian cancer aggressiveness and recurrence. Ovarian Cancer Advocacy Plans: A highly experienced ovarian cancer advocate, Ms. Jody Elliot, will participate as the ovarian cancer advocate in this research (Letter of Support attached). Ms. Elliot is an active participant in the Ray of Hope for Ovarian Cancer Cure, Inc. Ray of hope is a non-profit organization raise awareness and funds for the fight against ovarian cancer and to provide support for the warriors and their families. Ms. Elliot will bring the approaches she has used successfully in ovarian cancer advocacy to this grant. She will provide the patient perspective when research projects are designed and implemented and have been involved in all phases of the development of this proposal. Ms. Elliot will be actively involved in all aspects of the prop
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310311
Entities
People
- Pradeep Chaluvally-raghavan
Organizations
- Medical College of Wisconsin
- United States Army