Oncotarget

Research Papers:

Connexin 43 expression is associated with increased malignancy in prostate cancer cell lines and functions to promote migration

Ao Zhang, Masahiro Hitomi, Noah Bar-Shain, Zafardjan Dalimov, Leigh Ellis, Kiran K. Velpula, Gail C. Fraizer, Robert G. Gourdie and Justin D. Lathia _

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Oncotarget. 2015; 6:11640-11651. https://doi.org/10.18632/oncotarget.3449

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Abstract

Ao Zhang1,2, Masahiro Hitomi1,2, Noah Bar-Shain2, Zafardjan Dalimov3, Leigh Ellis3, Kiran K. Velpula4, Gail C. Fraizer5, Robert G. Gourdie6, Justin D. Lathia1,2,7

1Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, 44195, USA

2Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

3Genitourinary Program, Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo NY, 14263, USA

4Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, 61656, USA

5Department of Biological Sciences, Kent State University, Kent, OH, 44242, USA

6Center for Heart and Regenerative Medicine, Virginia Tech Carilion Research Institute, Roanoke, VA, 24016, USA

7Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA

Correspondence to:

Justin D. Lathia, e-mail: [email protected]

Keywords: Cx43, prostate cancer, invasion, gap junction independent function

Received: November 10, 2014     Accepted: February 24, 2015     Published: March 23, 2015

ABSTRACT

Impaired expression of connexins, the gap junction subunits that facilitate direct cell-cell communication, have been implicated in prostate cancer growth. To elucidate the crucial role of connexins in prostate cancer progression, we performed a systematic quantitative RT-PCR screening of connexin expression in four representative prostate cancer cell lines across the spectrum of malignancy. Transcripts of several connexin subunits were detected in all four cell lines, and connexin 43 (Cx43) showed marked elevation at both RNA and protein levels in cells with increased metastatic potential. Analysis of gap-junction-mediated intercellular communication revealed homocellular coupling in PC-3 cells, which had the highest Cx43 expression, with minimal coupling in LNCaP cells where Cx43 expression was very low. Treatment with the gap junction inhibitor carbenoxolone or connexin mimetic peptide ACT-1 did not impair cell growth, suggesting that growth is independent of functional gap junctions. PC-3 cells with Cx43 expression reduced by shRNA showed decreased migration in monolayer wound healing assay, as well as decreased transwell invasion capacities when compared to control cells expressing non-targeting shRNA. These results, together with the correlation between Cx43 expression levels and the metastatic capacity of the cell lines, suggest a role of Cx43 in prostate cancer invasion and metastasis.


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