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Two Faces of Cathepsin D: Physiological Guardian Angel and Pathological Demon.

Khalkhali-Ellis Z, Hendrix MJ - Biol Med (Aligarh) (2014)

Bottom Line: Specifically, deregulated synthesis, post-translational modifications and hyper-secretion of CatD, along with its mitogenic effects, are established hallmarks of cancer.This review outlines CatD's post-translational modifications, cellular trafficking, secretion and protein binding partners in normal mammary gland, and restates the "site-specific" function of CatD which is most probably dictated by its post-translational modifications and binding partners.Noteworthy, CatD's association with one of its binding partners in the context of drug sensitivity is highlighted, with the optimism that it could contribute to the development of more effective chemotherapeutic agent(s) tailored for individual patients.

View Article: PubMed Central - PubMed

Affiliation: Stanley Manne Children's Research Institute, Northwestern University Feinberg School of Medicine, 2300 Children's Plaza, Box 222, Chicago, Illinois, 60614-3394, USA.

ABSTRACT

Since its discovery as a lysosomal hydrolase, Cathepsin D (CatD) has been the subject of intensive scrutiny by numerous scientists. Those accumulated efforts have defined its biosynthetic pathway, structure, and companion proteins in the context of its perceived "house keeping" function. However, in the past two decades CatD has emerged as a multifunctional enzyme, involved in myriad biological processes beyond its original "housekeeping" role. CatD is responsible for selective and limited cleavage (quite distinct from non-specific protein degradation) of particular substrates vital to proper cellular function. These proteolytic events are critical in the control of biological processes, including cell cycle progression, differentiation and migration, morphogenesis and tissue remodeling, immunological processes, ovulation, fertilization, neuronal outgrowth, angiogenesis, and apoptosis. Consistent with the biological relevance of CatD, its deficiency, altered regulation or post-translational modification underlie important pathological conditions such as cancer, atherosclerosis, neurological and skin disorders. Specifically, deregulated synthesis, post-translational modifications and hyper-secretion of CatD, along with its mitogenic effects, are established hallmarks of cancer. More importantly, but less studied, is its significance in regulating the sensitivity to anticancer drugs. This review outlines CatD's post-translational modifications, cellular trafficking, secretion and protein binding partners in normal mammary gland, and restates the "site-specific" function of CatD which is most probably dictated by its post-translational modifications and binding partners. Noteworthy, CatD's association with one of its binding partners in the context of drug sensitivity is highlighted, with the optimism that it could contribute to the development of more effective chemotherapeutic agent(s) tailored for individual patients.

No MeSH data available.


Related in: MedlinePlus

Model depicting different routes of CatD trafficking in association with its binding partners in polarized normal mammary epithelial cells, and their relevance to cancer: 1). When in the Golgi, the Man-6-P tagged CatD binds Man-6-PR (and/or sortilin) and is transported to the endosomal compartment. In the acidic environment, the complex is dissociated and Man-6-PR returns to the membrane with the retromer complex, while CatD is cleaved and processed in the late endosome and lysosomes. 2). Under normal conditions ≤5% of pro-CatD (either alone or in a complex with Pro-Sap) is secreted from the ER. 3). In polarized epithelial cells, the basolateral release of CatD is also observed, the binding partner in this case is unknown. However, in Caco-2 colon epithelial cell line, Man-6PR binds CatD and transports it basolateraly. 4). Generation of ceramide by acid sphingomyelinase results in the limited permeability of lysosomal membrane and release of CatD, leading to the induction of apoptosis. The majority of these pathways are altered in breast cancer. In pathway 1, the reduced acidification of endosomal/lysosomal compartment noted in cancer cells affects proper processing of CatD, resulting in increased secretion of pro-CatD. Routes 2 and 3 are greatly elevated and could lead to excessive ECM degradation. Route 4 could be equally affected by changes in vacuolar acidification, which alters CatD processing, its lysosomal release and participation in apoptosis.
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Figure 3: Model depicting different routes of CatD trafficking in association with its binding partners in polarized normal mammary epithelial cells, and their relevance to cancer: 1). When in the Golgi, the Man-6-P tagged CatD binds Man-6-PR (and/or sortilin) and is transported to the endosomal compartment. In the acidic environment, the complex is dissociated and Man-6-PR returns to the membrane with the retromer complex, while CatD is cleaved and processed in the late endosome and lysosomes. 2). Under normal conditions ≤5% of pro-CatD (either alone or in a complex with Pro-Sap) is secreted from the ER. 3). In polarized epithelial cells, the basolateral release of CatD is also observed, the binding partner in this case is unknown. However, in Caco-2 colon epithelial cell line, Man-6PR binds CatD and transports it basolateraly. 4). Generation of ceramide by acid sphingomyelinase results in the limited permeability of lysosomal membrane and release of CatD, leading to the induction of apoptosis. The majority of these pathways are altered in breast cancer. In pathway 1, the reduced acidification of endosomal/lysosomal compartment noted in cancer cells affects proper processing of CatD, resulting in increased secretion of pro-CatD. Routes 2 and 3 are greatly elevated and could lead to excessive ECM degradation. Route 4 could be equally affected by changes in vacuolar acidification, which alters CatD processing, its lysosomal release and participation in apoptosis.

Mentions: The prediction of patient response to drug therapy is the ultimate goal of pharmacogenomics research. This is specifically important in cancer treatment, and instrumental in selecting effective chemotherapeutic agent tailored for individual patients. Unfortunately to date, the administration of ineffective chemotherapeutic agents often diminishes the quality of life for many cancer patients. Expression profile analyses have identified genes (specifically CatD) associated with sensitivity to anticancer drugs, however [94,95], the very complex nature of the drug response in a multi-organ system compared to single cells renders the clinical application of such findings quite challenging. The critical role of CatD in apoptosis [24–27], highlights a possible function for its binding partners in these processes. Our laboratory has exploited CatD partnership with Maspin to investigate such a possibility. IFN-γ is a widely used chemotherapeutic agent in many types of cancer; however, the majority of breast cancer cell lines are refractory to this cytokine [96, Z-Khalkhali-Ellis, unpublished observation]. This non-conformity was determined to be (at least in part) due to silencing of Maspin and deregulated expression and secretion of CatD [37]. Notably, IFN-γ reduces proliferation, changes vacuolar pH, alters CatD processing, and disrupts cell polarity, ultimately resulting in cell death. While, breast cancer cell lines devoid of Maspin are refractory to this cytokine. Maspin transfection of these cell lines reduces their pro-CatD secretion, and renders them responsive to IFN-γ(Figure 3).


Two Faces of Cathepsin D: Physiological Guardian Angel and Pathological Demon.

Khalkhali-Ellis Z, Hendrix MJ - Biol Med (Aligarh) (2014)

Model depicting different routes of CatD trafficking in association with its binding partners in polarized normal mammary epithelial cells, and their relevance to cancer: 1). When in the Golgi, the Man-6-P tagged CatD binds Man-6-PR (and/or sortilin) and is transported to the endosomal compartment. In the acidic environment, the complex is dissociated and Man-6-PR returns to the membrane with the retromer complex, while CatD is cleaved and processed in the late endosome and lysosomes. 2). Under normal conditions ≤5% of pro-CatD (either alone or in a complex with Pro-Sap) is secreted from the ER. 3). In polarized epithelial cells, the basolateral release of CatD is also observed, the binding partner in this case is unknown. However, in Caco-2 colon epithelial cell line, Man-6PR binds CatD and transports it basolateraly. 4). Generation of ceramide by acid sphingomyelinase results in the limited permeability of lysosomal membrane and release of CatD, leading to the induction of apoptosis. The majority of these pathways are altered in breast cancer. In pathway 1, the reduced acidification of endosomal/lysosomal compartment noted in cancer cells affects proper processing of CatD, resulting in increased secretion of pro-CatD. Routes 2 and 3 are greatly elevated and could lead to excessive ECM degradation. Route 4 could be equally affected by changes in vacuolar acidification, which alters CatD processing, its lysosomal release and participation in apoptosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4318633&req=5

Figure 3: Model depicting different routes of CatD trafficking in association with its binding partners in polarized normal mammary epithelial cells, and their relevance to cancer: 1). When in the Golgi, the Man-6-P tagged CatD binds Man-6-PR (and/or sortilin) and is transported to the endosomal compartment. In the acidic environment, the complex is dissociated and Man-6-PR returns to the membrane with the retromer complex, while CatD is cleaved and processed in the late endosome and lysosomes. 2). Under normal conditions ≤5% of pro-CatD (either alone or in a complex with Pro-Sap) is secreted from the ER. 3). In polarized epithelial cells, the basolateral release of CatD is also observed, the binding partner in this case is unknown. However, in Caco-2 colon epithelial cell line, Man-6PR binds CatD and transports it basolateraly. 4). Generation of ceramide by acid sphingomyelinase results in the limited permeability of lysosomal membrane and release of CatD, leading to the induction of apoptosis. The majority of these pathways are altered in breast cancer. In pathway 1, the reduced acidification of endosomal/lysosomal compartment noted in cancer cells affects proper processing of CatD, resulting in increased secretion of pro-CatD. Routes 2 and 3 are greatly elevated and could lead to excessive ECM degradation. Route 4 could be equally affected by changes in vacuolar acidification, which alters CatD processing, its lysosomal release and participation in apoptosis.
Mentions: The prediction of patient response to drug therapy is the ultimate goal of pharmacogenomics research. This is specifically important in cancer treatment, and instrumental in selecting effective chemotherapeutic agent tailored for individual patients. Unfortunately to date, the administration of ineffective chemotherapeutic agents often diminishes the quality of life for many cancer patients. Expression profile analyses have identified genes (specifically CatD) associated with sensitivity to anticancer drugs, however [94,95], the very complex nature of the drug response in a multi-organ system compared to single cells renders the clinical application of such findings quite challenging. The critical role of CatD in apoptosis [24–27], highlights a possible function for its binding partners in these processes. Our laboratory has exploited CatD partnership with Maspin to investigate such a possibility. IFN-γ is a widely used chemotherapeutic agent in many types of cancer; however, the majority of breast cancer cell lines are refractory to this cytokine [96, Z-Khalkhali-Ellis, unpublished observation]. This non-conformity was determined to be (at least in part) due to silencing of Maspin and deregulated expression and secretion of CatD [37]. Notably, IFN-γ reduces proliferation, changes vacuolar pH, alters CatD processing, and disrupts cell polarity, ultimately resulting in cell death. While, breast cancer cell lines devoid of Maspin are refractory to this cytokine. Maspin transfection of these cell lines reduces their pro-CatD secretion, and renders them responsive to IFN-γ(Figure 3).

Bottom Line: Specifically, deregulated synthesis, post-translational modifications and hyper-secretion of CatD, along with its mitogenic effects, are established hallmarks of cancer.This review outlines CatD's post-translational modifications, cellular trafficking, secretion and protein binding partners in normal mammary gland, and restates the "site-specific" function of CatD which is most probably dictated by its post-translational modifications and binding partners.Noteworthy, CatD's association with one of its binding partners in the context of drug sensitivity is highlighted, with the optimism that it could contribute to the development of more effective chemotherapeutic agent(s) tailored for individual patients.

View Article: PubMed Central - PubMed

Affiliation: Stanley Manne Children's Research Institute, Northwestern University Feinberg School of Medicine, 2300 Children's Plaza, Box 222, Chicago, Illinois, 60614-3394, USA.

ABSTRACT

Since its discovery as a lysosomal hydrolase, Cathepsin D (CatD) has been the subject of intensive scrutiny by numerous scientists. Those accumulated efforts have defined its biosynthetic pathway, structure, and companion proteins in the context of its perceived "house keeping" function. However, in the past two decades CatD has emerged as a multifunctional enzyme, involved in myriad biological processes beyond its original "housekeeping" role. CatD is responsible for selective and limited cleavage (quite distinct from non-specific protein degradation) of particular substrates vital to proper cellular function. These proteolytic events are critical in the control of biological processes, including cell cycle progression, differentiation and migration, morphogenesis and tissue remodeling, immunological processes, ovulation, fertilization, neuronal outgrowth, angiogenesis, and apoptosis. Consistent with the biological relevance of CatD, its deficiency, altered regulation or post-translational modification underlie important pathological conditions such as cancer, atherosclerosis, neurological and skin disorders. Specifically, deregulated synthesis, post-translational modifications and hyper-secretion of CatD, along with its mitogenic effects, are established hallmarks of cancer. More importantly, but less studied, is its significance in regulating the sensitivity to anticancer drugs. This review outlines CatD's post-translational modifications, cellular trafficking, secretion and protein binding partners in normal mammary gland, and restates the "site-specific" function of CatD which is most probably dictated by its post-translational modifications and binding partners. Noteworthy, CatD's association with one of its binding partners in the context of drug sensitivity is highlighted, with the optimism that it could contribute to the development of more effective chemotherapeutic agent(s) tailored for individual patients.

No MeSH data available.


Related in: MedlinePlus