This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Manna, P. P. Articles by Frazier, W. A. Search for Related Content PubMed PubMed Citation Articles by Manna, P. P. Articles by Frazier, W. A.

CD47 Mediates Killing of Breast Tumor Cells via Gi-Dependent Inhibition of Protein Kinase A

Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri

Thrombospondins (TSPs) have been implicated as antitumor and antimetastasis factors in breast cancer. Although this effect has been attributed to the antiangiogenic activity of TSPs, recent observations suggest other mechanisms may be at work. The TSP receptor CD47 (integrin-associated protein) has recently been reported to mediate a novel form of apoptosis. Here, we have studied the response of breast cancer cells to CD47 ligands TSP-1, the CD47 agonist peptide 4N1K derived from TSP-1, and the anti-CD47 monoclonal antibody 1F7. All of these ligands killed four different breast cancer cell lines. This CD47-mediated cell death did not require active caspases or Bcl-2 degradation and did not cause DNA laddering or cytochrome c release. Pertussis toxin (PTX) prevented CD47-mediated death, indicating the involvement of Gi. 4N1K dramatically reduced intracellular cAMP levels, an effect reversed with PTX. Forskolin, 8-bromo cAMP, and isobutylmethylxanthine (IBMX) all prevented CD47-mediated apoptosis, indicating the involvement of cAMP. H89 and protein kinase A (PKA) inhibitor peptide prevented rescue of breast cancer cells by PTX, 8-Br-cAMP, and forskolin, suggesting that the effects of cAMP are mediated via PKA-dependent phosphorylation events. Epidermal growth factor also inhibited CD47-induced apoptosis via a PKC-dependent but ERK-independent pathway. Thus, CD47-mediated killing of breast cancer cells occurs by a novel pathway involving regulation of cAMP levels by heterotrimeric Gi with subsequent effects mediated by PKA.

This article has been cited by other articles:

				C.-J. Lih, W. Wei, and S. N. Cohen Txr1: a transcriptional regulator of thrombospondin-1 that modulates cellular sensitivity to taxanes Genes & Dev., August 1, 2006; 20(15): 2082 - 2095. [Abstract] [Full Text] [PDF]

				P. P. Manna, J. Dimitry, P.-A. Oldenborg, and W. A. Frazier CD47 Augments Fas/CD95-mediated Apoptosis J. Biol. Chem., August 19, 2005; 280(33): 29637 - 29644. [Abstract] [Full Text] [PDF]

				A. Saumet, M. B. Slimane, M. Lanotte, J. Lawler, and V. Dubernard Type 3 repeat/C-terminal domain of thrombospondin-1 triggers caspase-independent cell death through CD47/{alpha}v{beta}3 in promyelocytic leukemia NB4 cells Blood, July 15, 2005; 106(2): 658 - 667. [Abstract] [Full Text] [PDF]

				R. H. Hastings, F. Araiza, D. W. Burton, M. Bedley, and L. J. Deftos Parathyroid hormone-related protein regulates apoptosis in lung cancer cells through protein kinase A Am J Physiol Cell Physiol, December 1, 2004; 287(6): C1616 - C1622. [Abstract] [Full Text] [PDF]

				L. Benetti and B. Roizman Herpes simplex virus protein kinase US3 activates and functionally overlaps protein kinase A to block apoptosis PNAS, June 22, 2004; 101(25): 9411 - 9416. [Abstract] [Full Text] [PDF]