Activation of cathepsin B, secreted by a colorectal cancer cell line requires low pH and is mediated by cathepsin D

Stappen, J. W. J. van der; Williams, Ann C.; Maciewicz, Rose A.; Paraskeva, Christos

doi:10.1002/(sici)1097-0215(19960807)67:4<547::aid-ijc14>3.0.co;2-4

Cited by 86 publications

(37 citation statements)

References 33 publications

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“…One of the major mechanisms involved in the acidification of intracellular organelles is the expression of vacuolar ATPases (19) markedly expressed and continuously activated in metastatic melanoma cells (18). Moreover, cathepsin B is among the proteolytic enzymes that are potently activated in acidic conditions (20), suggesting that metastatic melanoma cells are continuously predisposed to digest even complex materials through a vacuolar ATPases-mediated acidification of intracellular organelles, which in turn may maintain cathepsin B in an activated condition (20).…”

Section: Discussionmentioning

confidence: 99%

“…Then, we analyzed in melanoma cells the expression of proteolytic enzymes, including a set of proteases known to be activated in acidic conditions, such as cathepsin B and D (20). As revealed by flow cytometry analysis, metastatic melanoma cells displayed significantly (P < 0.01) higher levels of the cysteine endopeptidase cathepsin B compared with primary melanoma cells (Fig.…”

Section: Cannibal Cells Containing T Cells Are Detectable In Meta-mentioning

confidence: 98%

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Cannibalism of Live Lymphocytes by Human Metastatic but Not Primary Melanoma Cells

Lugini¹,

Matarrese²,

et al. 2006

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The phenomenon of cell cannibalism, which generally refers to the engulfment of cells within other cells, was described in malignant tumors, but its biological significance is still largely unknown. In the present study, we investigated the occurrence, the in vivo relevance, and the underlying mechanisms of cannibalism in human melanoma. As first evidence, we observed that tumor cannibalism was clearly detectable in vivo in metastatic lesions of melanoma and often involved T cells, which could be found in a degraded state within tumor cells. Then, in vitro experiments confirmed that cannibalism of T cells was a property of metastatic melanoma cells but not of primary melanoma cells. In particular, morphologic analyses, including time-lapse cinematography and electron microscopy, revealed a sequence of events, in which metastatic melanoma cells were able to engulf and digest live autologous melanoma-specific CD8 + T cells. Importantly, this cannibalistic activity significantly increased metastatic melanoma cell survival, particularly under starvation condition, supporting the evidence that tumor cells may use the eating of live lymphocytes as a way to ''feed'' in condition of low nutrient supply. The mechanism underlying cannibalism involved a complex framework, including lysosomal protease cathepsin B activity, caveolae formation, and ezrin cytoskeleton integrity and function. In conclusion, our study shows that human metastatic melanoma cells may eat live T cells, which are instead programmed to kill them, suggesting a novel mechanism of tumor immune escape. Moreover, our data suggest that cannibalism may represent a sort of ''feeding'' activity aimed at sustaining survival and progression of malignant tumor cells in an unfavorable microenvironment. (Cancer Res 2006; 66(7): 3629-38)

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Section: Discussionmentioning

confidence: 99%

Section: Cannibal Cells Containing T Cells Are Detectable In Meta-mentioning

confidence: 98%

Cannibalism of Live Lymphocytes by Human Metastatic but Not Primary Melanoma Cells

Lugini¹,

Matarrese²,

et al. 2006

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“…General protein degradation and turnover Many (including ↓) [36] Activation and degradation of polypeptide hormones, FGF [37] chemokines, growth factors and their receptors Plasminogen [38] Prolactin [39,40] Endostatin [41] Osteocalcin [42] Thyroglobulin [43] Insulin [44] Glucagon [45] IL-1 [46] IGFBP [47] Androgen receptor [48] Parathyroid hormone [49] MIP-1 alpha [50] MIP-1 beta [50] SLC [50] Activation of enzymatic precursors Cathepsin B [51,52] Cathepsin L [51,53] Transglutaminase 1 [54] Brain antigen processing Amyloid beta A4 protein [55,56] Tau [57] Tubulin [58] Myelin basic protein [59] Mhtt [60] Apolipoprotein E [61] Alpha-synuclein [62] Degradation of cytoskeletal proteins Neurofilaments [63] Actin [64,65] Myosin [64,66] Tropomyosin [65] Monocyte-mediated fibrinolysis Fibrinogen [67,68] Fibrin [67,68] Regulation of apoptosis Bid [69] Thiredoxin-1 [70] Processing of enzyme activators and inhibitors Prosaposin …”

Section: Biological Function Target Protein Referencementioning

confidence: 99%

Cathepsin D—Many functions of one aspartic protease

Beneš

Větvička

Fusek

2008

Critical Reviews in Oncology/Hematology

532

474

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For years, it has been held that cathepsin D (CD) is involved in rather nonspecific protein degradation in a strongly acidic milieu of lysosomes. Studies with CD knock-out mice revealed that CD is not necessary for embryonal development but it is indispensable for postnatal tissue homeostasis. Mutation that abolishes CD enzymatic activity causes neuronal ceroid lipofuscinosis (NCL) characterized by severe neurodegeneration, developmental regression, visual loss and epilepsy in both animals and humans.In the last decade, however, an increasing number of studies demonstrated that enzymatic function of CD is not restricted solely to acidic milieu of lysosomes with important consequences in regulation of apoptosis. In addition to CD enzymatic activity, it has been shown that apoptosis is also regulated by catalytically inactive mutants of CD which suggests that CD interacts with other important molecules and influences cell signaling.Moreover, procathepsin D, secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their pro-invasive and pro-metastatic properties. Numerous studies found that pCD/CD level represents an independent prognostic factor in a variety of cancers and is therefore considered to be a potential target of anti-cancer therapy.Studies dealing with functions of cathepsin D are complicated by the fact that there are several simultaneous forms of CD in a cell -pCD, intermediate enzymatically active CD and mature heavy and light chain CD. It became evident that these forms may differently regulate the above mentioned processes.In this article, we review the possible functions of CD and its various forms in cells and organisms during physiological and pathological conditions.

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“…18. Activation of proenzymes and inactivation of proteinase inhibitors by cathepsin D [123][124][125][126][127][128].…”

Section: Role In Protein Degradationmentioning

confidence: 99%

Human cathepsin D.

Minarowska

Gacko²,

Karwowska³

et al. 2008

Folia Histochem Cytobiol.

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Activation of cathepsin B, secreted by a colorectal cancer cell line requires low pH and is mediated by cathepsin D

Cited by 86 publications

References 33 publications

Cannibalism of Live Lymphocytes by Human Metastatic but Not Primary Melanoma Cells

Cannibalism of Live Lymphocytes by Human Metastatic but Not Primary Melanoma Cells

Cathepsin D—Many functions of one aspartic protease

Human cathepsin D.

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