Stromal-derived factor-1alpha induces a non-canonical pathway to activate the endocrine-linked Tac1 gene in non-tumorigenic breast cells.
The chemokine Stromal-derived factor-1alpha (SDF-1alpha) interacts with seven transmembrane (TM) G-protein-coupled receptor (GPR), CXCR4. SDF-1alpha is linked to inflammation, chemoattraction, cancer metastasis, and hematopoiesis. Tachykinin (Tac1) peptides bind seven transmembrane (TM), GPR and are involved in tumor promotion. SDF-1alpha regulates Tac1 expression in non-tumorigenic breast cells through a bimodal pattern with repression at high levels through nuclear factor-kappa B (NFkappaB) activation. This study focuses on the mechanism of activation at low SDF-1alpha in MCF12A non-tumorigenic breast cells. Reporter gene assays with the 5' flanking region of Tac1 (exon 1 omitted) and co-transfection with the repressor of cAMP response element (CREB) (ICER), and transfection with the CRE sites mutated, verified critical roles for CRE sites in SDF-1alpha-mediated Tac1 activation. Western blots and functional assays with specific inhibitors indicated that SDF-1alpha phosphorylated CREB (P-CREB) via Galpha(i)2-PI3K-protein kinase C (PKC)zeta-p38-extracellular signal-regulated kinase (ERK) and no evidence of cAMP-PKA pathway. This observation is different from previous studies that reported CREB-phosphorylated PKA pathway in the activation of Tac1 in bone marrow stromal cells. This suggests cell specificity in Tac1 expression. In conclusion, this study reports on a non-canonical pathway in Tac1 activation by SDF-1alpha. This finding is significant, since Tac1 is relevant to breast cancer metastasis, to bone marrow where stromal cells have a significant facilitating function.
Corcoran
Kelly E
KE
Department of Medicine-Hematology-Oncology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA.
Malhotra
Ashwani
A
Molina
Carlos A
CA
Rameshwar
Pranela
P
D024506:5' Flanking Region; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000494:pharmacology / Q000502:physiology*; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D015288:Neurokinin A / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
C115163:CREB1 protein, human; C497410:CREM protein, human; D054377:Chemokine CXCL12; D017362:Cyclic AMP Response Element-Binding Protein; D011498:Protein Precursors; D021122:Protein Subunits; D051786:Cyclic AMP Response Element Modulator; D015288:Neurokinin A; C081975:protein kinase C eta; D011493:Protein Kinase C