The Role of Cysteine Cathepsins in Cancer Progression and Drug Resistance

Rudzińska, Magdalena; Parodi, Alessandro; Soond, Surinder M.; Винаров, А.З.; Korolev, Dmitry; Morozov, Andrey; Daglioglu, Cenk; Tutar, Yusuf; Zamyatnin, Andrey A.

doi:10.3390/ijms20143602

Cited by 87 publications

(60 citation statements)

References 202 publications

(210 reference statements)

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“…The inhibition of CTSs has been widely explored over the last decades in the field of chronic inflammatory diseases [27,37,204,205], cardiovascular diseases [10,19,181], osteoporosis [70][71][72][73], arthritis [28,206], kidney diseases [30][31][32]84], pancreatitis [207], obesity [208][209][210], cancer [25,34,48,74,82,211], neurodegenerative diseases [39,41,184,185,212,213], and many other pathological states. Multiple inhibitors are currently available, ranging from reversible covalent inhibitors to irreversible inhibitors [214][215][216][217][218] (Table 4).…”

Section: Cathepsin Inhibitors and Their Therapeutic Applicationsmentioning

confidence: 99%

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Pasquale

Moles

Pavone

2020

Cells

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Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases.

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Section: Cathepsin Inhibitors and Their Therapeutic Applicationsmentioning

confidence: 99%

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Pasquale

Moles

Pavone

2020

Cells

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“…It has been noted that in cancer cells, cathepsin L is induced by MYC; moreover, cathepsin C is known to be up-regulated by MYC in TAMs [ 24 , 144 ]. Secreted cathepsins are involved in extracellular matrix degradation and remodeling, and cathepsins inside the cells are part of the signaling pathways involved in cancer cell growth and inflammation [ 69 , 70 ]. In the past, the main focus of the studies on cathepsins in tumor invasion had been simply based on their role in ECM degradation, although the spectrum of cathepsin proteases functions is much broader.…”

Section: Myc–a Key Player In the Tumor Microenvironment (Tme)mentioning

confidence: 99%

MYC as a Multifaceted Regulator of Tumor Microenvironment Leading to Metastasis

Meškytė

Keskas

Ciribilli

2020

IJMS

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The Myc family of oncogenes is deregulated in many types of cancer, and their over-expression is often correlated with poor prognosis. The Myc family members are transcription factors that can coordinate the expression of thousands of genes. Among them, c-Myc (MYC) is the gene most strongly associated with cancer, and it is the focus of this review. It regulates the expression of genes involved in cell proliferation, growth, differentiation, self-renewal, survival, metabolism, protein synthesis, and apoptosis. More recently, novel studies have shown that MYC plays a role not only in tumor initiation and growth but also has a broader spectrum of functions in tumor progression. MYC contributes to angiogenesis, immune evasion, invasion, and migration, which all lead to distant metastasis. Moreover, MYC is able to promote tumor growth and aggressiveness by recruiting stromal and tumor-infiltrating cells. In this review, we will dissect all of these novel functions and their involvement in the crosstalk between tumor and host, which have demonstrated that MYC is undoubtedly the master regulator of the tumor microenvironment. In sum, a better understanding of MYC’s role in the tumor microenvironment and metastasis development is crucial in proposing novel and effective cancer treatment strategies.

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“…Cysteine cathepsins released in the tumor microenvironment (TME) promote tumorigenesis in several ways, e.g., by processing different growth factors, cytokines, and chemokines; by cleaving cell-cell junction proteins; or by remodeling the extracellular matrix (ECM) [8,9]. They also play a role in many other tumor-suppressing processes, such as cell death and autophagy, which can contribute to worsening by the development of drug resistance [10].…”

Section: Introductionmentioning

confidence: 99%

Conditional Gene Targeting Reveals Cell Type-Specific Roles of the Lysosomal Protease Cathepsin L in Mammary Tumor Progression

Parigiani

Ketscher

Timme

et al. 2020

Cancers

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Background: Cathepsin L (Ctsl) is a cysteine protease mainly located within the endosomal/lysosomal cell compartment. High expression of Ctsl indicates poor prognosis in human breast cancer. However, the cell type-specific Ctsl functions responsible for this association remain elusive. Methods: Because constitutive Ctsl−/− mice develop a complex phenotype, we developed a conditional model allowing for cell type-specific inactivation of Ctsl in mammary epithelium or myeloid cells in the transgenic mouse mammary tumor virus (MMTV)-polyoma middle T (PyMT) breast cancer model. Results: Ctsl ablation in mammary epithelial cells resulted in delayed initiation and end-stage of cancers. The latter displayed large dead cell areas. Inducible in vitro deletion of Ctsl in MMTV-PyMT-derived breast cancer cells revealed expansion of the acidic cell compartment, alteration of intracellular amino acid levels, and impaired mTOR signaling. In consequence, Ctsl-deficient cells exhibited slow growth rates and high apoptosis susceptibility. In contrast to Ctsl-deficient mammary epithelium, selective knockout of Ctsl in myeloid cells had no effects on primary tumors, but promoted lung metastasis formation. Conclusions: Our cell type-specific in vivo analysis provides strong evidence for a cancer cell-intrinsic, tumor-promoting role of Ctsl in primary breast cancer, whereas metastasis is negatively regulated by Ctsl expressed by bone marrow-derived cells.

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The Role of Cysteine Cathepsins in Cancer Progression and Drug Resistance

Cited by 87 publications

References 202 publications

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

MYC as a Multifaceted Regulator of Tumor Microenvironment Leading to Metastasis

Conditional Gene Targeting Reveals Cell Type-Specific Roles of the Lysosomal Protease Cathepsin L in Mammary Tumor Progression

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