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Article ; Online: Improving CME: using participant satisfaction measures to specify educational methods.

Olivieri, Jason J / Regala, Roderick P

The Journal of continuing education in the health professions

2013 Volume 33, Issue 2, Page(s) 146–147

MeSH term(s)	Education, Medical, Continuing/methods ; Education, Medical, Continuing/standards ; Educational Measurement ; Humans ; Patient Satisfaction ; Quality Assurance, Health Care/standards
Language	English
Publishing date	2013
Publishing country	United States
Document type	Journal Article
ZDB-ID	639445-0
ISSN	1554-558X ; 0894-1912
ISSN (online)	1554-558X
ISSN	0894-1912
DOI	10.1002/chp.21176
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Article: Protein kinase C iota: human oncogene, prognostic marker and therapeutic target.

Fields, Alan P / Regala, Roderick P

Pharmacological research

2007 Volume 55, Issue 6, Page(s) 487–497

Abstract: The protein kinase C (PKC) family of serine/threonine kinases has been the subject of intensive study in the field of cancer since their initial discovery as major cellular receptors for the tumor promoting phorbol esters nearly 30 years ago. However, ... ...

Abstract	The protein kinase C (PKC) family of serine/threonine kinases has been the subject of intensive study in the field of cancer since their initial discovery as major cellular receptors for the tumor promoting phorbol esters nearly 30 years ago. However, despite these efforts, the search for a direct genetic link between members of the PKC family and human cancer has yielded only circumstantial evidence that any PKC isozyme is a true cancer gene. This situation changed in the past year with the discovery that atypical protein kinase C iota (PKC iota) is a bonafide human oncogene. PKC iota is required for the transformed growth of human cancer cells and the PKC iota gene is the target of tumor-specific gene amplification in multiple forms of human cancer. PKC iota participates in multiple aspects of the transformed phenotype of human cancer cells including transformed growth, invasion and survival. Herein, we review pertinent aspects of atypical PKC structure, function and regulation that relate to the role of these enzymes in oncogenesis. We discuss the evidence that PKC iota is a human oncogene, review mechanisms controlling PKC iota expression in human cancers, and describe the molecular details of PKC iota-mediated oncogenic signaling. We conclude with a discussion of how oncogenic PKC iota signaling has been successfully targeted to identify a novel, mechanism-based therapeutic drug currently entering clinical trials for treatment of human lung cancer. Throughout, we identify key unanswered questions and exciting future avenues of investigation regarding this important oncogenic molecule.
MeSH term(s)	Animals ; Biomarkers, Tumor/biosynthesis ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/physiology ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/enzymology ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Female ; Gene Amplification ; Gold Sodium Thiomalate/pharmacology ; Gold Sodium Thiomalate/therapeutic use ; Humans ; Isoenzymes/biosynthesis ; Isoenzymes/genetics ; Isoenzymes/physiology ; Lung Neoplasms/drug therapy ; Lung Neoplasms/enzymology ; Lung Neoplasms/pathology ; Oncogenes ; Ovarian Neoplasms/enzymology ; Protein Kinase C/biosynthesis ; Protein Kinase C/genetics ; Protein Kinase C/physiology ; Protein Structure, Tertiary
Chemical Substances	Biomarkers, Tumor ; Isoenzymes ; Gold Sodium Thiomalate (12244-57-4) ; protein kinase C zeta (EC 2.7.11.1) ; Protein Kinase C (EC 2.7.11.13) ; protein kinase C lambda (EC 2.7.11.13)
Language	English
Publishing date	2007-05-05
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1003347-6
ISSN	1096-1186 ; 1043-6618 ; 0031-6989
ISSN (online)	1096-1186
ISSN	1043-6618 ; 0031-6989
DOI	10.1016/j.phrs.2007.04.015
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Article ; Online: Atypical protein kinase C iota expression and aurothiomalate sensitivity in human lung cancer cells.

Regala, Roderick P / Thompson, E Aubrey / Fields, Alan P

Cancer research

2008 Volume 68, Issue 14, Page(s) 5888–5895

Abstract: The antirheumatoid agent aurothiomalate (ATM) is a potent inhibitor of oncogenic PKC iota. ATM inhibits non-small lung cancer (NSCLC) growth by binding PKC iota and blocking activation of a PKC iota-Par6-Rac1-Pak-Mek 1,2-Erk 1,2 signaling pathway. Here, ... ...

Abstract	The antirheumatoid agent aurothiomalate (ATM) is a potent inhibitor of oncogenic PKC iota. ATM inhibits non-small lung cancer (NSCLC) growth by binding PKC iota and blocking activation of a PKC iota-Par6-Rac1-Pak-Mek 1,2-Erk 1,2 signaling pathway. Here, we assessed the growth inhibitory activity of ATM in a panel of human cell lines representing major lung cancer subtypes. ATM inhibited anchorage-independent growth in all lines tested with IC(50)s ranging from approximately 300 nmol/L to >100 micromol/L. ATM sensitivity correlates positively with expression of PKC iota and Par6, but not with the PKC iota binding protein p62, or the proposed targets of ATM in rheumatoid arthritis (RA), thioredoxin reductase 1 or 2. PKC iota expression profiling revealed that a significant subset of primary NSCLC tumors express PKC iota at or above the level associated with ATM sensitivity. ATM sensitivity is not associated with general sensitivity to the cytotoxic agents cis-platin, placitaxel, and gemcitabine. ATM inhibits tumorigenicity of both sensitive and insensitive lung cell tumors in vivo at plasma drug concentrations achieved in RA patients undergoing ATM therapy. ATM inhibits Mek/Erk signaling and decreases proliferative index without effecting tumor apoptosis or vascularization in vivo. We conclude that ATM exhibits potent antitumor activity against major lung cancer subtypes, particularly tumor cells that express high levels of the ATM target PKC iota and Par6. Our results indicate that PKC iota expression profiling will be useful in identifying lung cancer patients most likely to respond to ATM therapy in an ongoing clinical trial.
MeSH term(s)	Animals ; Antirheumatic Agents/therapeutic use ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/enzymology ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Gene Expression Profiling ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Gold Sodium Thiomalate/therapeutic use ; Humans ; Inhibitory Concentration 50 ; Isoenzymes/biosynthesis ; Isoenzymes/genetics ; Lung Neoplasms/drug therapy ; Lung Neoplasms/enzymology ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Protein Kinase C/biosynthesis ; Protein Kinase C/genetics
Chemical Substances	Antirheumatic Agents ; Isoenzymes ; Gold Sodium Thiomalate (12244-57-4) ; Protein Kinase C (EC 2.7.11.13) ; protein kinase C lambda (EC 2.7.11.13)
Language	English
Publishing date	2008-07-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-08-0438
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Article ; Online: Atypical protein kinase C{iota} is required for bronchioalveolar stem cell expansion and lung tumorigenesis.

Regala, Roderick P / Davis, Rebecca K / Kunz, Alyssa / Khoor, Andras / Leitges, Michael / Fields, Alan P

Cancer research

2009 Volume 69, Issue 19, Page(s) 7603–7611

Abstract: Protein kinase Ciota (PKCiota) is an oncogene required for maintenance of the transformed phenotype of non-small cell lung cancer cells. However, the role of PKCiota in lung tumor development has not been investigated. To address this question, we ... ...

Abstract	Protein kinase Ciota (PKCiota) is an oncogene required for maintenance of the transformed phenotype of non-small cell lung cancer cells. However, the role of PKCiota in lung tumor development has not been investigated. To address this question, we established a mouse model in which oncogenic Kras(G12D) is activated by Cre-mediated recombination in the lung with or without simultaneous genetic loss of the mouse PKCiota gene, Prkci. Genetic loss of Prkci dramatically inhibits Kras-initiated hyperplasia and subsequent lung tumor formation in vivo. This effect correlates with a defect in the ability of Prkci-deficient bronchioalveolar stem cells to undergo Kras-mediated expansion and morphologic transformation in vitro and in vivo. Furthermore, the small molecule PKCiota inhibitor aurothiomalate inhibits Kras-mediated bronchioalveolar stem cell expansion and lung tumor growth in vivo. Thus, Prkci is required for oncogene-induced expansion and transformation of tumor-initiating lung stem cells. Furthermore, aurothiomalate is an effective antitumor agent that targets the tumor-initiating stem cell niche in vivo. These data have important implications for PKCiota as a therapeutic target and for the clinical use of aurothiomalate for lung cancer treatment.
MeSH term(s)	Animals ; Bronchioles/enzymology ; Bronchioles/pathology ; Carcinoma, Non-Small-Cell Lung/enzymology ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Transformation, Neoplastic/drug effects ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Genes, ras/drug effects ; Gold Sodium Thiomalate/pharmacology ; Humans ; Isoenzymes/deficiency ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Lung Neoplasms/enzymology ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Male ; Mice ; Mice, Transgenic ; Protein Kinase C/deficiency ; Protein Kinase C/genetics ; Protein Kinase C/metabolism ; Pulmonary Alveoli/enzymology ; Pulmonary Alveoli/pathology ; Stem Cells/enzymology ; Stem Cells/pathology
Chemical Substances	Isoenzymes ; Gold Sodium Thiomalate (12244-57-4) ; Protein Kinase C (EC 2.7.11.13) ; protein kinase C lambda (EC 2.7.11.13)
Language	English
Publishing date	2009-09-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-09-2066
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Article ; Online: Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential.

Justilien, Verline / Regala, Roderick P / Tseng, I-Chu / Walsh, Michael P / Batra, Jyotica / Radisky, Evette S / Murray, Nicole R / Fields, Alan P

PloS one

2012 Volume 7, Issue 4, Page(s) e35040

Abstract: Matrix metalloproteinases (Mmps) stimulate tumor invasion and metastasis by degrading the extracellular matrix. Here we reveal an unexpected role for Mmp10 (stromelysin 2) in the maintenance and tumorigenicity of mouse lung cancer stem-like cells (CSC). ... ...

Abstract	Matrix metalloproteinases (Mmps) stimulate tumor invasion and metastasis by degrading the extracellular matrix. Here we reveal an unexpected role for Mmp10 (stromelysin 2) in the maintenance and tumorigenicity of mouse lung cancer stem-like cells (CSC). Mmp10 is highly expressed in oncosphere cultures enriched in CSCs and RNAi-mediated knockdown of Mmp10 leads to a loss of stem cell marker gene expression and inhibition of oncosphere growth, clonal expansion, and transformed growth in vitro. Interestingly, clonal expansion of Mmp10 deficient oncospheres can be restored by addition of exogenous Mmp10 protein to the culture medium, demonstrating a direct role for Mmp10 in the proliferation of these cells. Oncospheres exhibit enhanced tumor-initiating and metastatic activity when injected orthotopically into syngeneic mice, whereas Mmp10-deficient cultures show a severe defect in tumor initiation. Conversely, oncospheres implanted into syngeneic non-transgenic or Mmp10(-/-) mice show no significant difference in tumor initiation, growth or metastasis, demonstrating the importance of Mmp10 produced by cancer cells rather than the tumor microenvironment in lung tumor initiation and maintenance. Analysis of gene expression data from human cancers reveals a strong positive correlation between tumor Mmp10 expression and metastatic behavior in many human tumor types. Thus, Mmp10 is required for maintenance of a highly tumorigenic, cancer-initiating, metastatic stem-like cell population in lung cancer. Our data demonstrate for the first time that Mmp10 is a critical lung cancer stem cell gene and novel therapeutic target for lung cancer stem cells.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Gene Expression Regulation, Neoplastic ; Humans ; Lung/enzymology ; Lung/metabolism ; Lung/pathology ; Lung Neoplasms/enzymology ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Matrix Metalloproteinase 10/genetics ; Matrix Metalloproteinase 10/metabolism ; Mice ; Mice, Inbred C57BL ; Neoplasm Metastasis/genetics ; Neoplasm Metastasis/pathology ; Neoplastic Stem Cells/enzymology ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Tumor Microenvironment
Chemical Substances	Matrix Metalloproteinase 10 (EC 3.4.24.22)
Language	English
Publishing date	2012-04-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0035040
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Article ; Online: Matrix metalloproteinase-10 promotes Kras-mediated bronchio-alveolar stem cell expansion and lung cancer formation.

Regala, Roderick P / Justilien, Verline / Walsh, Michael P / Weems, Capella / Khoor, Andras / Murray, Nicole R / Fields, Alan P

PloS one

2011 Volume 6, Issue 10, Page(s) e26439

Abstract: Matrix metalloproteinase 10 (MMP-10; stromelysin 2) is a member of a large family of structurally related matrix metalloproteinases, many of which have been implicated in tumor progression, invasion and metastasis. We recently identified Mmp10 as a gene ... ...

Abstract	Matrix metalloproteinase 10 (MMP-10; stromelysin 2) is a member of a large family of structurally related matrix metalloproteinases, many of which have been implicated in tumor progression, invasion and metastasis. We recently identified Mmp10 as a gene that is highly induced in tumor-initiating lung bronchioalveolar stem cells (BASCs) upon activation of oncogenic Kras in a mouse model of lung adenocarcinoma. However, the potential role of Mmp10 in lung tumorigenesis has not been addressed. Here, we demonstrate that Mmp10 is overexpressed in lung tumors induced by either the smoke carcinogen urethane or oncogenic Kras. In addition, we report a significant reduction in lung tumor number and size after urethane exposure or genetic activation of oncogenic Kras in Mmp10 null (Mmp10(-/-)) mice. This inhibitory effect is reflected in a defect in the ability of Mmp10-deficient BASCs to expand and undergo transformation in response to urethane or oncogenic Kras in vivo and in vitro, demonstrating a role for Mmp10 in the tumor-initiating activity of Kras-transformed lung stem cells. To determine the potential relevance of MMP10 in human cancer we analyzed Mmp10 expression in publicly-available gene expression profiles of human cancers. Our analysis reveals that MMP10 is highly overexpressed in human lung tumors. Gene set enhancement analysis (GSEA) demonstrates that elevated MMP10 expression correlates with both cancer stem cell and tumor metastasis genomic signatures in human lung cancer. Finally, Mmp10 is elevated in many human tumor types suggesting a widespread role for Mmp10 in human malignancy. We conclude that Mmp10 plays an important role in lung tumor initiation via maintenance of a highly tumorigenic, cancer-initiating, stem-like cell population, and that Mmp10 expression is associated with stem-like, highly metastatic genotypes in human lung cancers. These results indicate that Mmp10 may represent a novel therapeutic approach to target lung cancer stem cells.
MeSH term(s)	Animals ; Bronchi/pathology ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/pathology ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/enzymology ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Matrix Metalloproteinase 10/genetics ; Matrix Metalloproteinase 10/metabolism ; Mice ; Mice, Inbred C57BL ; Neoplasm Metastasis ; Proto-Oncogene Proteins p21(ras)/metabolism ; Pulmonary Alveoli/pathology ; Reproducibility of Results ; Stem Cells/pathology ; Urethane
Chemical Substances	Urethane (3IN71E75Z5) ; Matrix Metalloproteinase 10 (EC 3.4.24.22) ; Hras protein, mouse (EC 3.6.5.2) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2011-10-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0026439
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Article: Atypical protein kinase Ciota plays a critical role in human lung cancer cell growth and tumorigenicity.

Regala, Roderick P / Weems, Capella / Jamieson, Lee / Copland, John A / Thompson, E Aubrey / Fields, Alan P

The Journal of biological chemistry

2005 Volume 280, Issue 35, Page(s) 31109–31115

Abstract: Atypical protein kinase C (aPKC) isozymes function in epithelial cell polarity, proliferation, and survival and have been implicated in cellular transformation. However, the role of these enzymes in human cancer is largely unexplored. Here, we report ... ...

Abstract	Atypical protein kinase C (aPKC) isozymes function in epithelial cell polarity, proliferation, and survival and have been implicated in cellular transformation. However, the role of these enzymes in human cancer is largely unexplored. Here, we report that aPKCiota is highly expressed in human non-small cell lung cancer cell lines, whereas the closely related aPKC isozyme PKCzeta is undetectable in these cells. Disruption of PKCiota signaling reveals that PKCiota is dispensable for adherent growth of non-small cell lung cancer cells but is required for transformed growth in soft agar in vitro and for tumorigenicity in vivo. Molecular dissection of signaling down-stream of PKCiota demonstrates that Rac1 is a critical molecular target for PKCiota-dependent transformation, whereas PKCiota is not necessary for NFkappaB activation in vitro or in vivo. Expression of the PB1 domain of PKCiota (PKCiota-(1-113)) blocks PKCiota-dependent Rac1 activity and inhibits cellular transformation indicating a role for this domain in the transforming activity of PKCiota. Taken together, our data demonstrate that PKCiota is a critical lung cancer gene that activates a Rac1-->Pak-->Mek1,2-->Erk1,2 signaling pathway required for transformed growth. Our data indicate that PKCiota may be an attractive molecular target for mechanism-based therapies for treatment of lung cancer.
MeSH term(s)	Animals ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; Humans ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Mice ; Mice, Nude ; NF-kappa B/metabolism ; Neoplasm Transplantation ; Protein Kinase C/genetics ; Protein Kinase C/metabolism ; Signal Transduction/physiology ; rac1 GTP-Binding Protein/metabolism
Chemical Substances	Isoenzymes ; NF-kappa B ; Protein Kinase C (EC 2.7.11.13) ; protein kinase C lambda (EC 2.7.11.13) ; rac1 GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2005-07-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M505402200
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Article: A novel small-molecule inhibitor of protein kinase Ciota blocks transformed growth of non-small-cell lung cancer cells.

Stallings-Mann, Melody / Jamieson, Lee / Regala, Roderick P / Weems, Capella / Murray, Nicole R / Fields, Alan P

Cancer research

2006 Volume 66, Issue 3, Page(s) 1767–1774

Abstract: We recently showed that atypical protein kinase Ciota (PKCiota) is required for transformed growth of human non-small-cell lung cancer (NSCLC) cells by activating Rac1. Genetic disruption of PKCiota signaling blocks Rac1 activity and transformed growth, ... ...

Abstract	We recently showed that atypical protein kinase Ciota (PKCiota) is required for transformed growth of human non-small-cell lung cancer (NSCLC) cells by activating Rac1. Genetic disruption of PKCiota signaling blocks Rac1 activity and transformed growth, indicating that PKCiota is a viable target for development of novel therapeutics for NSCLC. Here, we designed and implemented a novel fluorescence resonance energy transfer-based assay to identify inhibitors of oncogenic PKCiota signaling. This assay was used to identify compounds that disrupt the interaction between PKCiota and its downstream effector Par6, which links PKCiota to Rac1. We identified aurothioglucose (ATG), a gold compound used clinically to treat rheumatoid arthritis, and the related compound, aurothiomalate (ATM), as potent inhibitors of PKCiota-Par6 interactions in vitro (IC(50) approximately 1 micromol/L). ATG blocks PKCiota-dependent signaling to Rac1 and inhibits transformed growth of NSCLC cells. ATG-mediated inhibition of transformation is relieved by expression of constitutively active Rac1, consistent with a mechanism at the level of the interaction between PKCiota and Par6. ATG inhibits A549 cell tumor growth in nude mice, showing efficacy against NSCLC in a relevant preclinical model. Our data show the utility of targeting protein-protein interactions involving PKCiota for antitumor drug development and provide proof of concept that chemical disruption of PKCiota signaling can be an effective treatment for NSCLC. ATG and ATM will be useful reagents for studying PKCiota function in transformation and represent promising new agents for the clinical treatment of NSCLC.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Animals ; Aurothioglucose/pharmacology ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/enzymology ; Carcinoma, Non-Small-Cell Lung/pathology ; Carrier Proteins/metabolism ; Cell Growth Processes/drug effects ; Cell Line, Tumor ; Female ; Fluorescence Resonance Energy Transfer ; Gold Sodium Thiomalate/pharmacology ; Humans ; Isoenzymes/antagonists & inhibitors ; Isoenzymes/metabolism ; Lung Neoplasms/drug therapy ; Lung Neoplasms/enzymology ; Lung Neoplasms/pathology ; Mice ; Mice, Nude ; Protein Kinase C/antagonists & inhibitors ; Protein Kinase C/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Structure, Tertiary ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays ; rac1 GTP-Binding Protein/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Isoenzymes ; PARD6A protein, human ; Protein Kinase Inhibitors ; RAC1 protein, human ; Gold Sodium Thiomalate (12244-57-4) ; Aurothioglucose (2P2V9Q0E78) ; Protein Kinase C (EC 2.7.11.13) ; protein kinase C lambda (EC 2.7.11.13) ; rac1 GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2006-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-05-3405
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Article: Atypical protein kinase C iota is an oncogene in human non-small cell lung cancer.

Regala, Roderick P / Weems, Capella / Jamieson, Lee / Khoor, Andras / Edell, Eric S / Lohse, Christine M / Fields, Alan P

Cancer research

2005 Volume 65, Issue 19, Page(s) 8905–8911

Abstract: Protein kinase C (PKC) isozymes have long been implicated in carcinogenesis. However, little is known about the functional significance of these enzymes in human cancer. We recently showed that the atypical PKC (aPKC) isozyme PKCiota is overexpressed in ... ...

Abstract	Protein kinase C (PKC) isozymes have long been implicated in carcinogenesis. However, little is known about the functional significance of these enzymes in human cancer. We recently showed that the atypical PKC (aPKC) isozyme PKCiota is overexpressed in human non-small cell lung cancer (NSCLC) cells and that PKCiota plays a critical role in the transformed growth of the human lung adenocarcinoma A549 cell line in vitro and tumorigenicity in vivo. Here we provide compelling evidence that PKCiota is an oncogene in NSCLC based on the following criteria: (a) aPKCiota is overexpressed in the vast majority of primary NSCLC tumors; (b) tumor PKCiota expression levels predict poor survival in patients with NSCLC; (c) the PKCiota gene is frequently amplified in established NSCLC cell lines and primary NSCLC tumors; (d) gene amplification drives PKCiota expression in NSCLC cell lines and primary NSCLC tumors; and (e) disruption of PKCiota signaling with a dominant negative PKCiota allele blocks the transformed growth of human NSCLC cells harboring PKCiota gene amplification. Taken together, our data provide conclusive evidence that PKCiota is required for the transformed growth of NSCLC cells and that the PKCiota gene is a target for tumor-specific genetic alteration by amplification. Interestingly, PKCiota expression predicts poor survival in NSCLC patients independent of tumor stage. Therefore, PKCiota expression profiling may be useful in identifying early-stage NSCLC patients at elevated risk of relapse. Our functional data indicate that PKCiota is an attractive target for development of novel, mechanism-based therapeutics to treat NSCLC.
MeSH term(s)	Aged ; Aged, 80 and over ; Carcinoma, Non-Small-Cell Lung/enzymology ; Carcinoma, Non-Small-Cell Lung/genetics ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Female ; Gene Amplification ; Humans ; Isoenzymes/biosynthesis ; Isoenzymes/genetics ; Lung Neoplasms/enzymology ; Lung Neoplasms/genetics ; Male ; Middle Aged ; Oncogenes ; Protein Kinase C/biosynthesis ; Protein Kinase C/genetics
Chemical Substances	Isoenzymes ; Protein Kinase C (EC 2.7.11.13) ; protein kinase C lambda (EC 2.7.11.13)
Language	English
Publishing date	2005-10-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-05-2372
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