Lysosomes as targets for cancer therapy.

Tumor invasion and metastasis are associated with altered lysosomal trafficking and increased expression of the lysosomal proteases termed cathepsins. Emerging experimental evidence suggests that such alterations in lysosomes may form an "Achilles heel" for cancer cells by sensitizing them to death pathways involving lysosomal membrane permeabilization and the release of cathepsins into the cytosol. Here, we highlight recent results on cancer-related changes in the composition and function of lysosomes, focusing on possible implications for the development of novel cancer therapeutics that target tumor cell lysosomes.

[1]  J. Kos,et al.  Cysteine proteinases and their endogenous inhibitors: target proteins for prognosis, diagnosis and therapy in cancer (review). , 1998, Oncology reports.

[2]  Jiahuai Han,et al.  Susceptibility of Lysosomes to Rupture Is a Determinant for Plasma Membrane Disruption in Tumor Necrosis Factor Alpha-Induced Cell Death , 2003, Molecular and Cellular Biology.

[3]  G. Gores,et al.  Lysosomes in cell death , 2004, Oncogene.

[4]  C. Gondi,et al.  Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis , 2004, Oncogene.

[5]  J. Nylandsted,et al.  Heat Shock Protein 70 Promotes Cell Survival by Inhibiting Lysosomal Membrane Permeabilization , 2004, The Journal of experimental medicine.

[6]  E. C. Toescu Patching the membranes up ‐ new views on cellular healing , 2003, Journal of cellular and molecular medicine.

[7]  J. Pober,et al.  Inhibition of Phosphatidylinositol 3-Kinase Sensitizes Vascular Endothelial Cells to Cytokine-initiated Cathepsin-dependent Apoptosis* , 2003, Journal of Biological Chemistry.

[8]  J. Eaton,et al.  Lysosomal involvement in apoptosis. , 1998, Redox report : communications in free radical research.

[9]  Kane Se,et al.  The role of cathepsin L in malignant transformation. , 1990 .

[10]  D. Hanahan,et al.  Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. , 2004, Cancer cell.

[11]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[12]  Bonnie F. Sloane,et al.  Unraveling the role of proteases in cancer. , 2000, Clinica chimica acta; international journal of clinical chemistry.

[13]  J. Deussing,et al.  Towards Specific Functions of Lysosomal Cysteine Peptidases: Phenotypes of Mice Deficient for Cathepsin B or Cathepsin L , 2001, Biological chemistry.

[14]  M. Peter,et al.  NF‐κB protects from the lysosomal pathway of cell death , 2003, The EMBO Journal.

[15]  P Kronqvist,et al.  Cysteine proteinase inhibitor cystatin A in breast cancer. , 1998, Cancer research.

[16]  U. Felbor,et al.  Sensitization to the Lysosomal Cell Death Pathway upon Immortalization and Transformation , 2004, Cancer Research.

[17]  G. Tortora,et al.  Resistance to taxanes is induced by c‐erbB‐2 overexpression in human MCF‐10A mammary epithelial cells and is blocked by combined treatment with an antisense oligonucleotide targeting type I protein kinase A , 2000, International journal of cancer.

[18]  R. Myers,et al.  Selective Disruption of Lysosomes in HeLa Cells Triggers Apoptosis Mediated by Cleavage of Bid by Multiple Papain-like Lysosomal Cathepsins* , 2004, Journal of Biological Chemistry.

[19]  M. Jäättelä,et al.  Multiple cell death pathways as regulators of tumour initiation and progression , 2004, Oncogene.

[20]  M. Gottesman,et al.  The role of cathepsin L in malignant transformation. , 1990, Seminars in cancer biology.

[21]  J. Castro,et al.  Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[22]  C. de Duve Lysosomes revisited. , 1983, European journal of biochemistry.

[23]  Bonnie F. Sloane,et al.  Membrane association of cathepsin B can be induced by transfection of human breast epithelial cells with c-Ha-ras oncogene. , 1994, Journal of cell science.

[24]  A. Brech,et al.  Phosphoinositide 3-kinase regulates maturation of lysosomes in rat hepatocytes. , 2003, The Biochemical journal.