Abstract
Development of chemotherapy resistance is a major problem in ovarian cancer. One understudied mechanism of chemoresistance is the induction of quiescence, a reversible nonproliferative state. Unfortunately, little is known about regulators of quiescence. Here, we identify the master transcription factor nuclear factor of activated T cells cytoplasmic 4 (NFATC4) as a regulator of quiescence in ovarian cancer. NFATC4 is enriched in ovarian cancer stem-like cells and correlates with decreased proliferation and poor prognosis. Treatment of cancer cells with cisplatin resulted in NFATC4 nuclear translocation and activation of the NFATC4 pathway, while inhibition of the pathway increased chemotherapy response. Induction of NFATC4 activity resulted in a marked decrease in proliferation, G0 cell cycle arrest, and chemotherapy resistance, both in vitro and in vivo. Finally, NFATC4 drove a quiescent phenotype in part via downregulation of MYC. Together, these data identify NFATC4 as a driver of quiescence and a potential new target to combat chemoresistance in ovarian cancer.
Highlights
Every year approximately 240,000 women are diagnosed with ovarian cancer worldwide, and 140,200 succumb to the disease [1]
NFATC4 mRNA and activity are enriched in a population of slowly dividing cancer stem-like cells (CSCs)
We observed no significant increase in annexin V staining in IcNFATC4 cells versus inducible luciferase (ILuc) controls (Figure 5E)
Summary
Every year approximately 240,000 women are diagnosed with ovarian cancer worldwide, and 140,200 succumb to the disease [1]. Identifying and understanding mechanisms of chemotherapy resistance in ovarian cancer are essential for the development of new therapeutics to prevent relapse and improve overall survival. Because chemotherapy targets rapidly dividing cells, quiescent stem cells are innately resistant to these therapies [4]. Weinberg and colleagues proposed [11], these cells have enhanced tumor initiation capacity and the ability to both self-renew and asymmetrically divide [10, 12] These cells exhibit increased resistance to chemotherapy [10]. We demonstrate that the NFAT family member NFATC4 (coding for the NFAT3 protein) is upregulated in ovarian CSCs and in response to chemotherapy undergoes cytoplasm to nuclear translocation, resulting in subsequent activation of known NFATC4 target genes. Induction of NFATC4 conveyed growth arrest and chemoresistance both in vitro and in vivo, suggesting that NFATC4-driven quiescence is in part related to suppressed MYC activity, activation of NFATC4 results in suppression of MYC expression, and overexpression of MYC following induction of NFATC4 can partially rescue the quiescent phenotype
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