Sensitization to the Lysosomal Cell Death Pathway by Oncogene-Induced Down-regulation of Lysosome-Associated Membrane Proteins 1 and 2

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  • Nicole Fehrenbacher
    1Apoptosis Department and Centre for Genotoxic Stress Response, Institute for Cancer Biology, Danish Cancer Society;
  • Lone Bastholm
    2Institute of Molecular Pathology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark;
  • Thomas Kirkegaard-Sørensen
    1Apoptosis Department and Centre for Genotoxic Stress Response, Institute for Cancer Biology, Danish Cancer Society;
  • Bo Rafn
    1Apoptosis Department and Centre for Genotoxic Stress Response, Institute for Cancer Biology, Danish Cancer Society;
  • Trine Bøttzauw
    1Apoptosis Department and Centre for Genotoxic Stress Response, Institute for Cancer Biology, Danish Cancer Society;
  • Christina Nielsen
    1Apoptosis Department and Centre for Genotoxic Stress Response, Institute for Cancer Biology, Danish Cancer Society;
  • Ekkehard Weber
    3Institute of Physiological Chemistry, Medical Faculty, Martin-Luther-University Halle-Wittenberg, Halle, Germany; and
  • Senji Shirasawa
    4Department of Cell Biology, School of Medicine, Fukuoka University, Fukuoka, Japan
  • Tuula Kallunki
    1Apoptosis Department and Centre for Genotoxic Stress Response, Institute for Cancer Biology, Danish Cancer Society;
  • Marja Jäättelä
    1Apoptosis Department and Centre for Genotoxic Stress Response, Institute for Cancer Biology, Danish Cancer Society;

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<jats:title>Abstract</jats:title> <jats:p>Expression and activity of lysosomal cysteine cathepsins correlate with the metastatic capacity and aggressiveness of tumors. Here, we show that transformation of murine embryonic fibroblasts with v-H-ras or c-srcY527F changes the distribution, density, and ultrastructure of the lysosomes, decreases the levels of lysosome-associated membrane proteins (LAMP-1 and LAMP-2) in an extracellular signal-regulated kinase (ERK)- and cathepsin-dependent manner, and sensitizes the cells to lysosomal cell death pathways induced by various anticancer drugs (i.e., cisplatin, etoposide, doxorubicin, and siramesine). Importantly, K-ras and erbb2 elicit a similar ERK-mediated activation of cysteine cathepsins, cathepsin-dependent down-regulation of LAMPs, and increased drug sensitivity in human colon and breast carcinoma cells, respectively. Notably, reconstitution of LAMP levels by ectopic expression or by cathepsin inhibitors protects transformed cells against the lysosomal cell death pathway. Furthermore, knockdown of either lamp1 or lamp2 is sufficient to sensitize the cells to siramesine-induced cell death and photo-oxidation–induced lysosomal destabilization. Thus, the transformation-associated ERK-mediated up-regulation of cysteine cathepsin expression and activity leads to a decrease in the levels of LAMPs, which in turn contributes to the enhanced sensitivity of transformed cells to drugs that trigger lysosomal membrane permeabilization. These data indicate that aggressive cancers with high cysteine cathepsin levels are especially sensitive to lysosomal cell death pathways and encourage the further development of lysosome-targeting compounds for cancer therapy. [Cancer Res 2008;68(16):6623–33]</jats:p>

Journal

  • Cancer Research

    Cancer Research 68 (16), 6623-6633, 2008-08-12

    American Association for Cancer Research (AACR)

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