Pancreatic Cancer Cell Migration and Metastasis Is Regulated by Chemokine-Biased Agonism and Bioenergetic Signaling. Cancer Res 2015 Sep 01;75(17):3529-42
Date
09/04/2015Pubmed ID
26330165Pubmed Central ID
PMC4560104DOI
10.1158/0008-5472.CAN-14-2645Scopus ID
2-s2.0-84942898695 (requires institutional sign-in at Scopus site) 62 CitationsAbstract
Patients with pancreatic ductal adenocarcinoma (PDAC) invariably succumb to metastatic disease, but the underlying mechanisms that regulate PDAC cell movement and metastasis remain little understood. In this study, we investigated the effects of the chemokine gene CXCL12, which is silenced in PDAC tumors, yet is sufficient to suppress growth and metastasis when re-expressed. Chemokines like CXCL12 regulate cell movement in a biphasic pattern, with peak migration typically in the low nanomolar concentration range. Herein, we tested the hypothesis that the biphasic cell migration pattern induced by CXCL12 reflected a biased agonist bioenergetic signaling that might be exploited to interfere with PDAC metastasis. In human and murine PDAC cell models, we observed that nonmigratory doses of CXCL12 were sufficient to decrease oxidative phosphorylation and glycolytic capacity and to increase levels of phosphorylated forms of the master metabolic kinase AMPK. Those same doses of CXCL12 locked myosin light chain into a phosphorylated state, thereby decreasing F-actin polymerization and preventing cell migration in a manner dependent upon AMPK and the calcium-dependent kinase CAMKII. Notably, at elevated concentrations of CXCL12 that were insufficient to trigger chemotaxis of PDAC cells, AMPK blockade resulted in increased cell movement. In two preclinical mouse models of PDAC, administration of CXCL12 decreased tumor dissemination, supporting our hypothesis that chemokine-biased agonist signaling may offer a useful therapeutic strategy. Our results offer a mechanistic rationale for further investigation of CXCL12 as a potential therapy to prevent or treat PDAC metastasis.
Author List
Roy I, McAllister DM, Gorse E, Dixon K, Piper CT, Zimmerman NP, Getschman AE, Tsai S, Engle DD, Evans DB, Volkman BF, Kalyanaraman B, Dwinell MBAuthors
Michael B. Dwinell PhD Center Director, Professor in the Microbiology and Immunology department at Medical College of WisconsinDouglas B. Evans MD Chair, Professor in the Surgery department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdenocarcinomaAnimals
Carcinoma, Pancreatic Ductal
Cell Line, Tumor
Cell Movement
Chemokine CXCL12
Humans
Mice
Neoplasm Metastasis
Oxidative Phosphorylation
Protein Kinases
