title: PKK suppresses tumor growth and is decreased in squamous cell carcinoma of the skin.
abstract: Non-melanoma skin cancer represents the most common cancer in the United States. Squamous cell carcinoma (SCC) of the skin is a subtype of NMSC that shows a greater potential for invasion and metastasis. The current study identifies the protein kinase C-associated kinase (PKK), which is also known as the receptor-interacting protein kinase 4, as a suppressor of tumor growth in SCC of the skin. We show that expression of PKK is decreased in human SCC of the skin compared with normal skin. Further, suppression of PKK in human keratinocytes leads to increased cell proliferation. The use of RNA interference to reduce PKK expression in keratinocytes leads to an increase in S phase and in proteins that promote cell cycle progression. Consistent with the results obtained from cell culture, there is a marked increased tumorigenesis after PKK knockdown in a xenotransplant model and in soft agar assays. The loss of tumor suppression involves the NF-κB and p63 pathways. NF-κB is inhibited through inhibition of inhibitor of NF-κB kinase function and there is increased nuclear TP63 activity after PKK knockdown. This study opens new avenues both in the discovery of disease pathogenesis and for potential treatments.
authors.affiliation: Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA; James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA. Electronic address: brian_poligone@urmc.rochester.edu.
authors.forename: Brian
authors.initials: B
authors.lastname: Poligone
authors.affiliation: Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA; James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Gilmore
authors.affiliation: Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA.
authors.forename: Carolina V
authors.initials: CV
authors.lastname: Alexander
authors.affiliation: Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Oleksyn
authors.affiliation: Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gillespie
authors.affiliation: Department of Biomedical Genetics, University of Rochester School of Medicine, Rochester, New York, USA.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA; James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Sherrif F
authors.initials: SF
authors.lastname: Ibrahim
authors.affiliation: Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA; James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Alice P
authors.initials: AP
authors.lastname: Pentland
authors.affiliation: Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA; James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Brown
authors.affiliation: Department of Dermatology, University of Rochester School of Medicine, Rochester, New York, USA.
authors.forename: Luojing
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D002453:Cell Cycle; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: C081876:CKAP4 protein, human; D008565:Membrane Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; C417187:RIPK4 protein, human; D017346:Protein Serine-Threonine Kinases