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Cancer Cell International
Published in: Cancer Cell International 1/2007

Open Access 01-12-2007 | Primary research

Cathepsin L increases invasion and migration of B16 melanoma

Authors: Zhen Yang, James L Cox

Published in: Cancer Cell International | Issue 1/2007

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Abstract

Background

Most cancers express elevated protease levels which contribute to certain aspects of tumor behavior such as growth, metastatic spread, and angiogenesis. Elevation of the cathepsins of the cysteine protease family correlates with increased invasion of tumor cells. Cysteine proteases such as cathepsins B, H and L type participate in tumor cell invasion as extracellular proteases, yet are enzymes whose exact roles in metastasis are still being elucidated.

Methods

We have examined the role of cathepsin L in highly metastatic B16F10 murine melanoma cells through genetic antisense constructs of cathepsin L. The effects of cathepsin L antisense were examined for melanoma cell proliferation, invasion, migration and adhesion.

Results

Antisense expression of cathepsin L, while decreasing enzyme activity in cell lysates, did not influence cell proliferation. Cathepsin L contributed to melanoma cell invasion and also augmented melanoma cell migration. Further, we demonstrated the adhesion of cathepsin L down-regulated clones was unaltered to fibronectin, laminin, and collagen. Finally, the inhibition of melanoma cell migration via down-regulation of cathepsin L appears to be independent of cystatin C expression.

Conclusion

This study shows that cathepsin L facilitates high metastatic B16 melanoma cell invasion and migration. The mechanism of migration inhibition by decreased cathepsin L is independent of cystatin C levels. Since metastasis depends upon both the invasiveness and migration of tumor cells, cathepsin L may be a therapeutic target of strong clinical interest.
Appendix
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Literature
1.
Mignatti P, Rifkin DB: Biology and biochemistry of proteinases in tumor invasion. Physiol Rev. 1993, 73 (1): 161-195.PubMed
2.
Budihna M, Skrk J, Zakotnik B, Gabrijelcic D, Lindtner J: Prognostic value of total cathepsin B in invasive ductal carcinoma of the breast. Eur J Cancer. 1995, 31A (5): 661-664. 10.1016/0959-8049(94)00504-X.CrossRefPubMed
3.
Frohlich E, Mohrle M, Klessen C: Cathepsins in basal cell carcinomas: activity, immunoreactivity and mRNA staining of cathepsins B, D, H and L. Arch Dermatol Res. 2004, 295 (10): 411-421. 10.1007/s00403-003-0449-9.PubMed
4.
Frohlich E, Schlagenhauff B, Mohrle M, Weber E, Klessen C, Rassner G: Activity, expression, and transcription rate of the cathepsins B, D, H, and L in cutaneous malignant melanoma. Cancer. 2001, 91 (5): 972-982. 10.1002/1097-0142(20010301)91:5<972::AID-CNCR1087>3.0.CO;2-Q.CrossRefPubMed
5.
Werle B, Kraft C, Lah TT, Kos J, Schanzenbacher U, Kayser K, Ebert W, Spiess E: Cathepsin B in infiltrated lymph nodes is of prognostic significance for patients with nonsmall cell lung carcinoma. Cancer. 2000, 89 (11): 2282-2291. 10.1002/1097-0142(20001201)89:11<2282::AID-CNCR17>3.0.CO;2-4.CrossRefPubMed
6.
Niedergethmann M, Wostbrock B, Sturm JW, Willeke F, Post S, Hildenbrand R: Prognostic impact of cysteine proteases cathepsin B and cathepsin L in pancreatic adenocarcinoma. Pancreas. 2004, 29 (3): 204-211. 10.1097/00006676-200410000-00005.CrossRefPubMed
7.
Kirschke H, Barrett AJ, Rawlings ND: Proteinases 1: lysosomal cysteine proteinases. Protein Profile. 1995, 2 (14): 1581-1643.PubMed
8.
Kobayashi H, Ohi H, Sugimura M, Shinohara H, Fujii T, Terao T: Inhibition of in vitro ovarian cancer cell invasion by modulation of urokinase-type plasminogen activator and cathepsin B. Cancer Res. 1992, 52 (13): 3610-3614.PubMed
9.
Strojnik T, Kos J, Zidanik B, Golouh R, Lah T: Cathepsin B immunohistochemical staining in tumor and endothelial cells is a new prognostic factor for survival in patients with brain tumors. Clin Cancer Res. 1999, 5 (3): 559-567.PubMed
10.
Kirschke H, Eerola R, Hopsu-Havu VK, Bromme D, Vuorio E: Antisense RNA inhibition of cathepsin L expression reduces tumorigenicity of malignant cells. Eur J Cancer. 2000, 36 (6): 787-795. 10.1016/S0959-8049(00)00014-9.CrossRefPubMed
11.
Chambers AF, Colella R, Denhardt DT, Wilson SM: Increased expression of cathepsins L and B and decreased activity of their inhibitors in metastatic, ras-transformed NIH 3T3 cells. Mol Carcinog. 1992, 5 (3): 238-245. 10.1002/mc.2940050311.CrossRefPubMed
12.
Frade R, Rodrigues-Lima F, Huang S, Xie K, Guillaume N, Bar-Eli M: Procathepsin-L, a proteinase that cleaves human C3 (the third component of complement), confers high tumorigenic and metastatic properties to human melanoma cells. Cancer Res. 1998, 58 (13): 2733-2736.PubMed
13.
Ishidoh K, Kominami E: Gene regulation and extracellular functions of procathepsin L. Biol Chem. 1998, 379 (2): 131-135.PubMed
14.
Abrahamson M, Alvarez-Fernandez M, Nathanson CM: Cystatins. Biochem Soc Symp. 2003, 179-199.
15.
Cox JL, Sexton PS, Green TJ, Darmani NA: Inhibition of B16 melanoma metastasis by overexpression of the cysteine proteinase inhibitor cystatin C. Melanoma Res. 1999, 9 (4): 369-374. 10.1097/00008390-199908000-00005.CrossRefPubMed
16.
Ervin H, Cox JL: Late stage inhibition of hematogenous melanoma metastasis by cystatin C over-expression. Cancer Cell Int. 2005, 5 (1): 14-10.1186/1475-2867-5-14.PubMedCentralCrossRefPubMed
17.
Helene C, Toulme JJ: Specific regulation of gene expression by antisense, sense and antigene nucleic acids. Biochim Biophys Acta. 1990, 1049 (2): 99-125.CrossRefPubMed
18.
Joy AM, Beaudry CE, Tran NL, Ponce FA, Holz DR, Demuth T, Berens ME: Migrating glioma cells activate the PI3-K pathway and display decreased susceptibility to apoptosis. J Cell Sci. 2003, 116 (Pt 21): 4409-4417. 10.1242/jcs.00712.CrossRefPubMed
19.
Levicar N, Dewey RA, Daley E, Bates TE, Davies D, Kos J, Pilkington GJ, Lah TT: Selective suppression of cathepsin L by antisense cDNA impairs human brain tumor cell invasion in vitro and promotes apoptosis. Cancer Gene Ther. 2003, 10 (2): 141-151. 10.1038/sj.cgt.7700546.CrossRefPubMed
20.
Zajc I, Sever N, Bervar A, Lah TT: Expression of cysteine peptidase cathepsin L and its inhibitors stefins A and B in relation to tumorigenicity of breast cancer cell lines. Cancer Lett. 2002, 187 (1-2): 185-190. 10.1016/S0304-3835(02)00452-4.CrossRefPubMed
21.
Lorenzo K, Ton P, Clark JL, Coulibaly S, Mach L: Invasive properties of murine squamous carcinoma cells: secretion of matrix-degrading cathepsins is attributable to a deficiency in the mannose 6-phosphate/insulin-like growth factor II receptor. Cancer Res. 2000, 60 (15): 4070-4076.PubMed
22.
Ulbricht B, Henny H, Horstmann H, Spring H, Faigle W, Spiess E: Influence of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) on the localization of cathepsin B and cathepsin L in human lung tumor cells. Eur J Cell Biol. 1997, 74 (3): 294-301.PubMed
23.
Qian F, Bajkowski AS, Steiner DF, Chan SJ, Frankfater A: Expression of five cathepsins in murine melanomas of varying metastatic potential and normal tissues. Cancer Res. 1989, 49 (17): 4870-4875.PubMed
24.
Yagel S, Warner AH, Nellans HN, Lala PK, Waghorne C, Denhardt DT: Suppression by cathepsin L inhibitors of the invasion of amnion membranes by murine cancer cells. Cancer Res. 1989, 49 (13): 3553-3557.PubMed
25.
Gondi CS, Kandhukuri N, Kondraganti S, Gujrati M, Olivero WC, Dinh DH, Rao JS: Down-regulation of uPAR and cathepsin B retards cofilin dephosphorylation. Int J Oncol. 2006, 28 (3): 633-639.PubMedCentralPubMed
26.
Krueger S, Kellner U, Buehling F, Roessner A: Cathepsin L antisense oligonucleotides in a human osteosarcoma cell line: effects on the invasive phenotype. Cancer Gene Ther. 2001, 8 (7): 522-528. 10.1038/sj.cgt.7700341.CrossRefPubMed
27.
Rousselet N, Mills L, Jean D, Tellez C, Bar-Eli M, Frade R: Inhibition of tumorigenicity and metastasis of human melanoma cells by anti-cathepsin L single chain variable fragment. Cancer Res. 2004, 64 (1): 146-151. 10.1158/0008-5472.CAN-03-1717.CrossRefPubMed
28.
Sokol JP, Schiemann WP: Cystatin C antagonizes transforming growth factor beta signaling in normal and cancer cells. Mol Cancer Res. 2004, 2 (3): 183-195.PubMed
29.
Boike G, Lah T, Sloane BF, Rozhin J, Honn K, Guirguis R, Stracke ML, Liotta LA, Schiffmann E: A possible role for cysteine proteinase and its inhibitors in motility of malignant melanoma and other tumour cells. Melanoma Res. 1992, 1 (5-6): 333-340.CrossRefPubMed
30.
Sexton PS, Cox JL: Inhibition of motility and invasion of B16 melanoma by the overexpression of cystatin C. Melanoma Res. 1997, 7 (2): 97-101. 10.1097/00008390-199704000-00002.CrossRefPubMed
31.
Goulet B, Baruch A, Moon NS, Poirier M, Sansregret LL, Erickson A, Bogyo M, Nepveu A: A cathepsin L isoform that is devoid of a signal peptide localizes to the nucleus in S phase and processes the CDP/Cux transcription factor. Mol Cell. 2004, 14 (2): 207-219. 10.1016/S1097-2765(04)00209-6.CrossRefPubMed
32.
Reiser J, Oh J, Shirato I, Asanuma K, Hug A, Mundel TM, Honey K, Ishidoh K, Kominami E, Kreidberg JA, Tomino Y, Mundel P: Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and alpha3 integrin. J Biol Chem. 2004, 279 (33): 34827-34832. 10.1074/jbc.M401973200.CrossRefPubMed
33.
Choong PF, Nadesapillai AP: Urokinase plasminogen activator system: a multifunctional role in tumor progression and metastasis. Clin Orthop Relat Res. 2003, S46-58. 10.1097/01.blo0000093845.72468.bd.
34.
Troen BR, Gal S, Gottesman MM: Sequence and expression of the cDNA for MEP (major excreted protein), a transformation-regulated secreted cathepsin. Biochem J. 1987, 246 (3): 731-735.PubMedCentralCrossRefPubMed
35.
Sambrook J FEF: Molecular Cloning: A Laboratory Manual. 1989, Cold Spring Harbor, NY , Cold Spring Harbor Laboratory
36.
Alonso S, Minty A, Bourlet Y, Buckingham M: Comparison of three actin-coding sequences in the mouse; evolutionary relationships between the actin genes of warm-blooded vertebrates. J Mol Evol. 1986, 23 (1): 11-22. 10.1007/BF02100994.CrossRefPubMed
37.
Lees MB, Paxman S: Modification of the Lowry procedure for the analysis of proteolipid protein. Anal Biochem. 1972, 47 (1): 184-192. 10.1016/0003-2697(72)90291-6.CrossRefPubMed
Metadata
Title
Cathepsin L increases invasion and migration of B16 melanoma
Authors
Zhen Yang
James L Cox
Publication date
01-12-2007
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2007
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/1475-2867-7-8

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