1. Notch1-mediated tumor suppression in cervical cancer with the involvement of SST signaling and its application in enhanced SSTR-targeted therapeutics.
- Author
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Franko-Tobin LG, Mackey LV, Huang W, Song X, Jin B, Luo J, Morris LM, Liu M, Fuselier JA, Coy DH, Wu L, and Sun L
- Subjects
- Animals, Cell Cycle Checkpoints, Cell Proliferation, Colforsin pharmacology, Cyclic AMP metabolism, Female, HeLa Cells, Humans, Mice, Receptors, Somatostatin antagonists & inhibitors, Uterine Cervical Neoplasms pathology, Receptor, Notch1 physiology, Receptors, Somatostatin physiology, Signal Transduction physiology, Somatostatin physiology, Uterine Cervical Neoplasms prevention & control
- Abstract
The role of Notch signaling in cervical cancer is seemingly controversial. To confirm the function of Notch signaling in this type of cancer, we established a stable Notch1-activated cervical cancer HeLa cell line. We found that Notch1 activation resulted in apoptosis, cell cycle arrest, and tumor suppression. At the molecular level, we found that a variety of genes associated with cyclic AMP, G protein-coupled receptor, and cancer signaling pathways contributed to Notch1-mediated tumor suppression. We observed that the expression of somatostatin (SST) was dramatically induced by Notch1 signaling activation, which was accompanied by enhanced expression of the cognate SST receptor subtype 1 (SSTR1) and SSTR2. Certain genes, such as tumor protein 63 (TP63, p63), were upregulated, whereas others, such as B-cell lymphoma 2 (BCL-2), Myc, Akt, and STAT3, were downregulated. Subsequently, knockdown of Notch1-induced SST reversed Notch1-induced decrease of BCL-2 and increase of p63, indicating that Notch1-induced tumor suppression may be partly through upregulating SST signaling. Our findings support a possible crosstalk between Notch signaling and SST signaling. Moreover, Notch-induced SSTR activation could enhance SSTR-targeted cancer chemotherapy. Valproic acid (VPA), a histone deacetylase inhibitor, suppressed cell growth and upregulated the expression of Notch1 and SSTR2. A combination therapy with VPA and the SSTR2-targeting cytotoxic conjugate CPT-SST strongly led to greater suppression, as compared to each alone. Our findings thus provide us with a promising clinical opportunity for enhanced cancer therapy using combinations of Notch1-activating agents and SSTR2-targeting agents. more...
- Published
- 2012
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