title: Prolactin signaling enhances colon cancer stemness by modulating Notch signaling in a Jak2-STAT3/ERK manner.
abstract: Prolactin (PRL) is a secretory cytokine produced by various tissues. Binding to the cognate PRL receptor (PRLR), it activates intracellular signaling via janus kinase (JAK), extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT) proteins. PRL regulates diverse activities under normal and abnormal conditions, including malignancies. Previous clinical data suggest serum PRL levels are elevated in colorectal cancer (CRC) patients. In this study, we first determined the expression of PRL and PRLR in colon cancer tissue and cell lines. Higher levels of PRLR expression were observed in the cancer cells and cell lines compared with normal colonic epithelial cells. Incubation of colon cancer cells with PRL-induced JAK2, STAT3 and ERK1/2 phosphorylation and increased expression of Jagged 1, which is a Notch-1 receptor ligand. Notch signaling regulates CRC stem cell population. We observed increased accumulation of the cleaved/active form of Notch-1 receptor (Notch intracellular domain) and increased expression of Notch responsive genes HEY1, HES1 and stem cell marker genes DCLK1, LGR5, ALDH1 and CD44. Finally, inhibiting PRL induced JAK2-STAT3 and JAK2-ERK1/2 using AG490 and PD98059, respectively, leads to complete abrogation of Notch signaling, suggesting a role for this pathway in regulating CRC stem cells. Together, our results demonstrate that cytokine signaling induced by PRL is active in colorectal cancers and may provide a novel target for therapeutic intervention.
authors.affiliation: Department of Molecular and Integrative Physiology.
authors.forename: Naveen K
authors.initials: NK
authors.lastname: Neradugomma
authors.forename: Dharmalingam
authors.initials: D
authors.lastname: Subramaniam
authors.forename: Ossama W
authors.initials: OW
authors.lastname: Tawfik
authors.forename: Vincent
authors.initials: V
authors.lastname: Goffin
authors.forename: T Rajendra
authors.initials: TR
authors.lastname: Kumar
authors.forename: Roy A
authors.initials: RA
authors.lastname: Jensen
authors.forename: Shrikant
authors.initials: S
authors.lastname: Anant
mesh_terms: D001483:Base Sequence; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017931:DNA Primers; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011388:Prolactin / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; D011388:Prolactin; D053614:Janus Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases