1. Department of Pharmacy, The Fifth People's Hospital of Shanghai, Fudan University; 801 He-Qing Rd., Shanghai 200240, China;
2. Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, University of South China, Hengyang, 421001, China;
3. State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai 200433, China;
4. Department of Medicine, School of Medicine, Tulane Health Sciences Center, New Orleans, LA 70112-2699, USA.
Cervical cancer is a second leading cancer death in women world-wide, with most cases in less developed countries. Notch signaling is highly conserved with its involvement in many cancers. In the present study, we established stable cervical cell lines with Notch activation and inactivation and found that Notch activation played a suppressive role in cervical cancer cells. Meanwhile, the transient overexpression of the active intracellular domain of all four Notch receptors (ICN1, 2, 3, and 4) also induced the suppression of cervical cancer Hela cell growth. ICN1 also induced cell cycle arrest at phase G1. Notch1 signaling activation affected the expression of serial genes, especially the genes associated with cAMP signaling, with an increase of genes like THBS1, VCL, p63, c-Myc and SCG2, a decrease of genes like NR4A2, PCK2 and BCL-2. Particularly,
The nuclear receptor NR4A2 was observed to induce cell proliferation via MTT assay and reduce cell apoptosis via FACS assay. Furthermore, NR4A2's activation could reverse ICN1-induced suppression of cell growth while erasing ICN1-induced increase of tumor suppressor p63. These findings support that Notch signaling mediates cervical cancer cell growth suppression with the involvement of nuclear receptor NR4A2. Notably, Notch/NR4A2/p63 signaling cascade possibly is a new signling pathway undisclosed.
Keywords: cervical cancer, cell proliferation, cell apoptosis, Notch signaling, nuclear receptor NR4A2, tumor suppressor p63.