Enhanced aggressiveness of benzopyrene-induced squamous carcinomas in transgenic mice overexpressing the proprotein convertase PACE4 (PCSK6).
PACE4 (PCSK6) is a proprotein convertase (PC) capable of processing numerous substrates involved in tumor growth, invasion, and metastasis. Because of the human relevancy of the tobacco-associated carcinogen benzo[a]pyrene (B(a)P) we investigated whether transgenic mice in which this PC is targeted to the epidermis (K5-PACE4) may be more susceptible to B(a)P complete carcinogenesis than wild type (WT) mice. In an in vitro experiment, using cell lines derived from skin tumors obtained after B(a)P treatment, we observed that PACE4 overexpression and activity accounts for an increased proliferation rate, exaggerated sensitivity to the PC inhibitor CMK, and interference with IGF-1R autophosphorylation. Squamous cell carcinomas, obtained from K5-PACE4 mice subjected to complete chemical carcinogenesis, were characterized by a 50% increase in cell proliferation, when compared with similar tumors from WT mice. In addition, tumors from K5-PACE4 mice showed deeper invasion into the underlying dermis. Thus, mice overexpressing PACE4 exhibited tumors of increased growth rate and invasive potential when exposed to the human carcinogen B(a)P, further supporting the significance of PCs in tumor growth and progression.
Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.|Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Daniel E
DE
Bassi
Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Jonathan
J
Cenna
Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Jirong
J
Zhang
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Edna
E
Cukierman
Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.|Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Andres J
AJ
Klein-Szanto
D000818:Animals; D001580:Benzopyrenes / Q000494:pharmacology*; D063646:Carcinogenesis / Q000139:chemically induced / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic / Q000378:metabolism*; D043484:Proprotein Convertases / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology
D001580:Benzopyrenes; D002273:Carcinogens; D017526:Receptor, IGF Type 1; C513086:Pcsk6 protein, mouse; D043484:Proprotein Convertases
PACE4; PCSK6; bezo(a)pyrene; proprotein convertases; skin carcinogenesis; squamous cell carcinoma; tumor progression