title: Cathepsin L inhibition by the small molecule KGP94 suppresses tumor microenvironment enhanced metastasis associated cell functions of prostate and breast cancer cells.
abstract: Metastasis remains the major cause of therapeutic failure, poor prognosis and high mortality in breast and prostate cancer patients. Aberrant microenvironments including hypoxia and acidic pH are common features of most solid tumors that have been long associated with enhanced metastasis and poor patient outcomes. Novel approaches to reduce metastatic incidences and improve overall survival of cancer patients clearly are needed. The crucial role of Cathepsin L (CTSL) in the dissemination of tumor cells has led to the development of novel cathepsin L inhibition strategies. The present study evaluated the ability of KGP94, a small molecule inhibitor of CTSL, to impair the metastatic phenotype of prostate (PC-3ML) and breast (MDA-MB-231) cancer cells both under normal and aberrant microenvironmental conditions. To assess the role of CTSL in hypoxia and acidosis triggered metastasis associated cell functions, secreted CTSL levels were determined under conditions pertinent to the tumor microenvironment. Acute exposures to hypoxic or acidic conditions significantly elevated secreted CTSL levels either through an increase in intracellular CTSL levels or through activation of lysosomal exocytosis or both, depending on the tumor type. Increases in CTSL secretion closely paralleled enhanced tumor cell migration and invasion suggesting that CTSL could be an essential factor in tumor microenvironment triggered metastasis. Importantly, KGP94 treatment led to marked attenuation of tumor cell invasion and migration under both normal and aberrant microenvironmental conditions suggesting that it may have significant utility as an anti-metastatic agent.
authors.affiliation: Department of Pharmacology and Therapeutics, Cancer and Genetics Research Complex, College of Medicine, University of Florida, Room 485E, Gainesville, FL, 32610, USA, dhivyasudhan@ufl.edu.
authors.forename: Dhivya R
authors.initials: DR
authors.lastname: Sudhan
authors.forename: Dietmar W
authors.initials: DW
authors.lastname: Siemann
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D056668:Cathepsin L / Q000037:antagonists & inhibitors*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D013882:Thiosemicarbazones / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: C581086:KGP94; D013882:Thiosemicarbazones; D056668:Cathepsin L; D013890:Thiourea