A protease inhibitor specifically inhibits growth of HPV-infected keratinocytes.
Protease inhibitors have been known to exhibit anticarcinogenic activity in a variety of model systems, although the biological target(s) and mechanism remain enigmatic. Human papillomavirus (HPV) is the primary etiological agent of cervical cancer. Here we show that a nuclear chymotrypsin-like protease activity (NCLPA), which appears to be involved in transformation in several different experimental models, is significantly elevated in keratinocytes infected with high-risk HPV. Further, we demonstrate a marked growth inhibition of organotypic raft cultures, which is specific for cells infected with high-risk HPV types, using a chloromethyl ketone inhibitor previously shown to be relatively selective for the NCLPA. Surprisingly, this HPV-dependent inhibitory effect is independent of any alterations in the NCLPA. This finding has clear implications for the development of novel therapeutics specifically targeted to cervical dysplasias with HPV-infected cells.
The Jake Gittlen Cancer Research Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
David A
DA
Drubin
Margaret E
ME
McLaughlin-Drubin
Gary A
GA
Clawson
Craig
C
Meyers
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology; D018929:Cell Culture Techniques; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002918:Chymotrypsin / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D016679:Genome, Viral; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D027383:Papillomaviridae / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity*; D030361:Papillomavirus Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000473:pathology
D000590:Amino Acid Chloromethyl Ketones; D009842:Oligopeptides; D011480:Protease Inhibitors; C083541:succinyl-alanylalanyl-prolyl-phenylalanine chloromethylketone; D010447:Peptide Hydrolases; D002918:Chymotrypsin; D004121:Dimethyl Sulfoxide