title: Notch1-mediated tumor suppression in cervical cancer with the involvement of SST signaling and its application in enhanced SSTR-targeted therapeutics.
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.
authors.affiliation: Department of Medicine, Peptide Research Laboratories, Tulane Health Sciences Center, New Orleans, Louisiana 70112, USA.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Franko-Tobin
authors.forename: L Vienna
authors.initials: LV
authors.lastname: Mackey
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Song
authors.forename: Baofeng
authors.initials: B
authors.lastname: Jin
authors.forename: Jing
authors.initials: J
authors.lastname: Luo
authors.forename: Lynsie M
authors.initials: LM
authors.lastname: Morris
authors.forename: Minqiu
authors.initials: M
authors.lastname: Liu
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fuselier
authors.forename: David H
authors.initials: DH
authors.lastname: Coy
authors.forename: Lizi
authors.initials: L
authors.lastname: Wu
authors.forename: Lichun
authors.initials: L
authors.lastname: Sun
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D051881:Receptor, Notch1 / Q000502:physiology*; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013004:Somatostatin / Q000502:physiology*; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000517:prevention & control*
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D017481:Receptors, Somatostatin; D005576:Colforsin; D013004:Somatostatin; D000242:Cyclic AMP