Understanding the Role of the Alternative NF-kB and MAPK Pathways in Maintaining Quiescence in Ovarian Cancer Stem-like Cells

Committee Members

• Dr. Carrie D. House (Chair), SDSU
• Dr. Teresa Monkkonen, Biology
• Dr. Christal Sohl, Chemistry

Abstract

Ovarian cancer stands as the deadliest gynecological cancer in the United States, and despite an initial positive response to chemotherapy, most patients with advanced stages of the disease ultimately experience relapse.

Recent research indicates that a subset of tumor cells known as Cancer Stem-like Cells (CSCs) exhibit resistance to treatment and contribute to recurrence. Key signaling pathways, particularly MAPK and NF-ĸB, play significant roles in tumor initiation, progression, and drug resistance in ovarian cancer.

Our previous findings demonstrated that the classical NF-ĸB factor, RELA, primarily facilitates cell proliferation, while the alternative factor, RELB, is associated with promoting quiescence. Furthermore, the activation of MAPK/ERK has been linked to the proliferation of ovarian cancer cells. Although both NF-ĸB and MAPK signaling pathways are essential for tumor progression, their specific functions in sustaining CSCs remain poorly understood. Initial in vivo experiments revealed that knocking down RELB alone after chemotherapy did not prevent the regrowth of residual tumors, whereas targeting RELA or inhibiting MAPK effectively curtailed regrowth.

Notably, the combination of RELB knockdown and MAPK inhibition resulted in a similar reduction in tumor regrowth as seen with RELA knockdown or MAPK inhibition alone. This led us to hypothesize that RELB aids in maintaining quiescence in CSCs by downregulating MAPK activity.

Our study found that RELB knockdown increased MAPK activity in two high-grade serous ovarian cancer cell lines, and cell cycle analyses indicated heightened proliferation with RELB knockdown, which was counteracted by MAPK inhibition. Additionally, the loss of RELB was associated with a decrease in quiescent cells, reinforcing its role in sustaining quiescence.

Collectively, these results suggest that RELB downregulates MAPK signaling to promote quiescence in ovarian CSCs, enhancing our understanding of the NF-ĸB and MAPK pathways in cell cycle regulation.