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 Kiley, S. C. Articles by Jaken, S. Search for Related Content PubMed PubMed Citation Articles by Kiley, S. C. Articles by Jaken, S.

Protein Kinase C Involvement in Mammary Tumor Cell Metastasis¹

Adirondack Biomedical Research Institute, Lake Placid, New York 12946 [S. C. K., K. J. C., M. G., S. J.], and Jake Gittlen Cancer Research Institute (C7810), Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033 [D. R. W., S. J.]

Metastasis requires cytoskeletal remodeling for migration, adhesion, and extravasation of metastatic cells. Although protein kinase C (PKC) is involved in tumor promotion/progression and cytoskeletal remodeling, its role in metastasis has not been defined. PKC levels are increased in highly metastatic 13762NF mammary tumor cells (MTLn3) compared with less metastatic, parental cell lines. To determine whether the increase in endogenous PKC is functionally related to their increased metastatic potential, we prepared MTLn3 cells that express the inhibitory regulatory domain fragment of PKC (RD) under the control of a tetracycline-inducible promoter. RD expression attenuated endogenous PKC activity, as demonstrated by decreased phosphorylation of the PKC substrate adducin in migrating cells. Thus, in MT cells, RD appears to primarily influence cytoskeleton-dependent processes rather than cell cycle progression. To determine whether RD expression influenced metastatic potential in vivo, MTLn3/RD cells were either grown in the mammary fat pad or injected into the tail vein of syngeneic rats, and effects of doxycycline-induced RD expression on pulmonary metastases were studied. Consistent with the in vitro data, induction of RD significantly reduced the number of lung metastases without affecting growth of the primary tumor. These results suggest that interfering with endogenous PKC activity by expressing the inhibitory RD fragment inhibits cytoskeleton-regulated processes important for MTLn3 cell metastasis.

This article has been cited by other articles:

				L. Huang, H.-C. Cheng, R. Isom, C.-S. Chen, R. A. Levine, and B. U. Pauli Protein Kinase C{epsilon} Mediates Polymeric Fibronectin Assembly on the Surface of Blood-borne Rat Breast Cancer Cells to Promote Pulmonary Metastasis J. Biol. Chem., March 21, 2008; 283(12): 7616 - 7627. [Abstract] [Full Text] [PDF]

				T. Uekita, L. Jia, M. Narisawa-Saito, J. Yokota, T. Kiyono, and R. Sakai CUB Domain-Containing Protein 1 Is a Novel Regulator of Anoikis Resistance in Lung Adenocarcinoma Mol. Cell. Biol., November 1, 2007; 27(21): 7649 - 7660. [Abstract] [Full Text] [PDF]

				S. Xia, L. W. Forman, and D. V. Faller Protein Kinase C{delta} Is Required for Survival of Cells Expressing Activated p21RAS J. Biol. Chem., May 4, 2007; 282(18): 13199 - 13210. [Abstract] [Full Text] [PDF]

				C.-L. Chen, Y.-T. Hsieh, and H.-C. Chen Phosphorylation of adducin by protein kinase C{delta} promotes cell motility J. Cell Sci., April 1, 2007; 120(7): 1157 - 1167. [Abstract] [Full Text] [PDF]

				F. Renault-Mihara, F. Beuvon, X. Iturrioz, B. Canton, S. De Bouard, N. Leonard, S. Mouhamad, A. Sharif, J. W. Ramos, M.-P. Junier, et al. Phosphoprotein Enriched in Astrocytes-15 kDa Expression Inhibits Astrocyte Migration by a Protein Kinase C{delta}-dependent Mechanism Mol. Biol. Cell, December 1, 2006; 17(12): 5141 - 5152. [Abstract] [Full Text] [PDF]

				M. J. van Nimwegen, M. Huigsloot, A. Camier, I. B. Tijdens, and B. van de Water Focal Adhesion Kinase and Protein Kinase B Cooperate to Suppress Doxorubicin-Induced Apoptosis of Breast Tumor Cells Mol. Pharmacol., October 1, 2006; 70(4): 1330 - 1339. [Abstract] [Full Text] [PDF]

				D. Alonso-Escolano, C. Medina, K. Cieslik, A. Radomski, P. Jurasz, M. J. Santos-Martinez, T. Jiffar, P. Ruvolo, and M. W. Radomski Protein Kinase C{delta} Mediates Platelet-Induced Breast Cancer Cell Invasion J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 373 - 380. [Abstract] [Full Text] [PDF]

				C. H. Nguyen and V. J. Watts Dexamethasone-Induced Ras Protein 1 Negatively Regulates Protein Kinase C {delta}: Implications for Adenylyl Cyclase 2 Signaling Mol. Pharmacol., May 1, 2006; 69(5): 1763 - 1771. [Abstract] [Full Text] [PDF]

				Y.-W. Qiang, K. Walsh, L. Yao, N. Kedei, P. M. Blumberg, J. S. Rubin, J. Shaughnessy Jr, and S. Rudikoff Wnts induce migration and invasion of myeloma plasma cells Blood, September 1, 2005; 106(5): 1786 - 1793. [Abstract] [Full Text] [PDF]

				J. B. Barry and V. Giguere Epidermal Growth Factor-Induced Signaling in Breast Cancer Cells Results in Selective Target Gene Activation by Orphan Nuclear Receptor Estrogen-Related Receptor {alpha} Cancer Res., July 15, 2005; 65(14): 6120 - 6129. [Abstract] [Full Text] [PDF]

				M. J. van Nimwegen, S. Verkoeijen, L. van Buren, D. Burg, and B. van de Water Requirement for Focal Adhesion Kinase in the Early Phase of Mammary Adenocarcinoma Lung Metastasis Formation Cancer Res., June 1, 2005; 65(11): 4698 - 4706. [Abstract] [Full Text] [PDF]

				A. I. Chernyavsky, J. Arredondo, L. M. Marubio, and S. A. Grando Differential regulation of keratinocyte chemokinesis and chemotaxis through distinct nicotinic receptor subtypes J. Cell Sci., November 1, 2004; 117(23): 5665 - 5679. [Abstract] [Full Text] [PDF]

				J. Zhang, P. Z. Anastasiadis, Y. Liu, E. A. Thompson, and A. P. Fields Protein Kinase C (PKC) {beta}II Induces Cell Invasion through a Ras/Mek-, PKC{iota}/Rac 1-dependent Signaling Pathway J. Biol. Chem., May 21, 2004; 279(21): 22118 - 22123. [Abstract] [Full Text] [PDF]

				D. N. JACKSON and D. A. FOSTER The enigmatic protein kinase C{delta}: complex roles in cell proliferation and survival FASEB J, April 1, 2004; 18(6): 627 - 636. [Abstract] [Full Text] [PDF]

				H.-D. Je, C. Gallant, P. C. Leavis, and K. G. Morgan Caveolin-1 regulates contractility in differentiated vascular smooth muscle Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H91 - H98. [Abstract] [Full Text] [PDF]

				Y.-W. Qiang, L. Yao, G. Tosato, and S. Rudikoff Insulin-like growth factor I induces migration and invasion of human multiple myeloma cells Blood, January 1, 2004; 103(1): 301 - 308. [Abstract] [Full Text] [PDF]

				M. Huigsloot, R. B. Tijdens, and B. van de Water Inhibition of Protein Kinase C{alpha} Enhances Anticancer Agent-Induced Loss of Anchorage-Independent Growth Regardless of Protection against Apoptosis by Bcl-2 Mol. Pharmacol., October 1, 2003; 64(4): 965 - 973. [Abstract] [Full Text] [PDF]

				M. A. McCracken, L. J. Miraglia, R. A. McKay, and J. S. Strobl Protein Kinase C {delta} Is a Prosurvival Factor in Human Breast Tumor Cell Lines Mol. Cancer Ther., March 1, 2003; 2(3): 273 - 281. [Abstract] [Full Text] [PDF]

				A. S. Clark, K. A. West, P. M. Blumberg, and P. A. Dennis Altered Protein Kinase C (PKC) Isoforms in Non-Small Cell Lung Cancer Cells: PKC{delta} Promotes Cellular Survival and Chemotherapeutic Resistance Cancer Res., February 15, 2003; 63(4): 780 - 786. [Abstract] [Full Text] [PDF]

				M. Huigsloot, I. B. Tijdens, G. J. Mulder, and B. van de Water Differential Regulation of Doxorubicin-induced Mitochondrial Dysfunction and Apoptosis by Bcl-2 in Mammary Adenocarcinoma (MTLn3) Cells J. Biol. Chem., September 20, 2002; 277(39): 35869 - 35879. [Abstract] [Full Text] [PDF]

				B. C. Morrish and M. G. Rumsby The 5' Untranslated Region of Protein Kinase C{delta} Directs Translation by an Internal Ribosome Entry Segment That Is Most Active in Densely Growing Cells and during Apoptosis Mol. Cell. Biol., September 1, 2002; 22(17): 6089 - 6099. [Abstract] [Full Text] [PDF]

				K. M. Lounsbury, M. Stern, D. Taatjes, S. Jaken, and B. T. Mossman Increased Localization and Substrate Activation of Protein Kinase C{delta} in Lung Epithelial Cells following Exposure to Asbestos Am. J. Pathol., June 1, 2002; 160(6): 1991 - 2000. [Abstract] [Full Text] [PDF]

				E. Joseloff, C. Cataisson, H. Aamodt, H. Ocheni, P. Blumberg, A. J. Kraker, and S. H. Yuspa Src Family Kinases Phosphorylate Protein Kinase C delta on Tyrosine Residues and Modify the Neoplastic Phenotype of Skin Keratinocytes J. Biol. Chem., March 29, 2002; 277(14): 12318 - 12323. [Abstract] [Full Text] [PDF]

				K. Podar, Y.-T. Tai, B. K. Lin, R. P. Narsimhan, M. Sattler, T. Kijima, R. Salgia, D. Gupta, D. Chauhan, and K. C. Anderson Vascular Endothelial Growth Factor-induced Migration of Multiple Myeloma Cells Is Associated with beta 1 Integrin- and Phosphatidylinositol 3-Kinase-dependent PKCalpha Activation J. Biol. Chem., March 1, 2002; 277(10): 7875 - 7881. [Abstract] [Full Text] [PDF]

				R. Massoumi, C. Larsson, and A. Sjolander Leukotriene D4 induces stress-fibre formation in intestinal epithelial cells via activation of RhoA and PKC{delta} J. Cell Sci., January 9, 2002; 115(17): 3509 - 3515. [Abstract] [Full Text] [PDF]

				S. Paruchuri, B. Hallberg, M. Juhas, C. Larsson, and A. Sjolander Leukotriene D4 activates MAPK through a Ras-independent but PKC{epsilon}-dependent pathway in intestinal epithelial cells J. Cell Sci., January 5, 2002; 115(9): 1883 - 1893. [Abstract] [Full Text] [PDF]

				M. L. Garcia-Bermejo, F. C. Leskow, T. Fujii, Q. Wang, P. M. Blumberg, M. Ohba, T. Kuroki, K.-C. Han, J. Lee, V. E. Marquez, et al. Diacylglycerol (DAG)-lactones, a New Class of Protein Kinase C (PKC) Agonists, Induce Apoptosis in LNCaP Prostate Cancer Cells by Selective Activation of PKCalpha J. Biol. Chem., January 4, 2002; 277(1): 645 - 655. [Abstract] [Full Text]

				K. Masur, K. Lang, B. Niggemann, K. S. Zanker, and F. Entschladen High PKC {alpha} and Low E-Cadherin Expression Contribute to High Migratory Activity of Colon Carcinoma Cells Mol. Biol. Cell, July 1, 2001; 12(7): 1973 - 1982. [Abstract] [Full Text] [PDF]

				R. Mandil, E. Ashkenazi, M. Blass, I. Kronfeld, G. Kazimirsky, G. Rosenthal, F. Umansky, P. S. Lorenzo, P. M. Blumberg, and C. Brodie Protein Kinase C{{alpha}} and Protein Kinase C{{delta}} Play Opposite Roles in the Proliferation and Apoptosis of Glioma Cells Cancer Res., June 1, 2001; 61(11): 4612 - 4619. [Abstract] [Full Text] [PDF]

				R. Palmantier, M. D. George, S. K. Akiyama, F. M. Wolber, K. Olden, and J. D. Roberts cis-Polyunsaturated Fatty Acids Stimulate {beta}1 Integrin-mediated Adhesion ofHuman Breast Carcinoma Cells to Type IV Collagen by Activating ProteinKinases C-{{epsilon}} and -{micro} Cancer Res., March 1, 2001; 61(6): 2445 - 2452. [Abstract] [Full Text]

				M. Sumitomo, R. Shen, J. S. Goldberg, J. Dai, D. Navarro, and D. M. Nanus Neutral Endopeptidase Promotes Phorbol Ester-induced Apoptosis in Prostate Cancer Cells by Inhibiting Neuropeptide-induced Protein Kinase C {{delta}} Degradation Cancer Res., December 1, 2000; 60(23): 6590 - 6596. [Abstract] [Full Text]

				T. Fujii, M. L. Garcia-Bermejo, J. L. Bernabo, J. Caamano, M. Ohba, T. Kuroki, L. Li, S. H. Yuspa, and M. G. Kazanietz Involvement of Protein Kinase C delta (PKCdelta ) in Phorbol Ester-induced Apoptosis in LNCaP Prostate Cancer Cells. LACK OF PROTEOLYTIC CLEAVAGE OF PKCdelta J. Biol. Chem., March 10, 2000; 275(11): 7574 - 7582. [Abstract] [Full Text] [PDF]

				I. Kronfeld, G. Kazimirsky, P. S. Lorenzo, S. H. Garfield, P. M. Blumberg, and C. Brodie Phosphorylation of Protein Kinase Cdelta on Distinct Tyrosine Residues Regulates Specific Cellular Functions J. Biol. Chem., November 3, 2000; 275(45): 35491 - 35498. [Abstract] [Full Text] [PDF]

				K. England, J. Watson, G. Beale, M. Warner, J. Cross, and M. Rumsby Signalling Pathways Regulating the Dephosphorylation of Ser729 in the Hydrophobic Domain of Protein Kinase Cepsilon upon Cell Passage J. Biol. Chem., March 23, 2001; 276(13): 10437 - 10442. [Abstract] [Full Text] [PDF]