Divergent roles of lysyl oxidase family members in ornithine decarboxylase- and RAS-transformed mouse fibroblasts and human melanoma cells

Kielosto, Mari; Eriksson, Johanna; Nummela, Pirjo; Yin, Miao; Hölttä, Erkki

doi:10.18632/oncotarget.26508

Cited by 5 publications

(5 citation statements)

References 92 publications

(126 reference statements)

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“…Such a difference in activities is also documented by recent publications. The involvement of one or more members of LOXs (in the active form or as the pro-peptide) was evaluated in different cancers and conditions: experimental ornithine decarboxylase-and RAS-transformed mouse fibroblasts and human melanoma cells, renal and bladder, and gastric cancers, respectively [91][92][93]. LOXs showed variability of expression during tumor development, with the possibility of exerting either promotion or even inhibition effects depending on the type of LOX expressed, the tumor type, and the microenvironment.…”

Section: Final Remarks and Conclusionmentioning

confidence: 99%

Lysyl oxidases: linking structures and immunity in the tumor microenvironment

Tenti

Vannucci

2019

Cancer Immunol Immunother

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The lysyl oxidases (LOXs) are a family of enzymes deputed to cross-link collagen and elastin, shaping the structure and strength of the extracellular matrix (ECM). However, many novel "non-canonical" functions, alternative substrates, and regulatory mechanisms have been described and are being continuously elucidated. The activity of LOXs, therefore, appears to be integrated into a complex network of signals regulating many cell functions, including survival/proliferation/differentiation. Among these signaling pathways, TGF-β and PI3K/Akt/mTOR, in particular, cross-talk extensively with each other and with LOXs also initiating complex feedback loops which modulate the activity of LOXs and direct the remodeling of the ECM. A growing body of evidence indicates that LOXs are not only important in the homeostasis of the normal structure of the ECM, but are also implicated in the establishment and maturation of the tumor microenvironment. LOXs' association with advanced and metastatic cancer is well established; however, there is enough evidence to support a significant role of LOXs in the transformation of normal epithelial cells, in the accelerated tumor development and the induction of invasion of the premalignant epithelium. A better understanding of LOXs and their interactions with the different elements of the tumor immune microenvironment will prove invaluable in the design of novel anti-tumor strategies.

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Section: Final Remarks and Conclusionmentioning

confidence: 99%

Lysyl oxidases: linking structures and immunity in the tumor microenvironment

Tenti

Vannucci

2019

Cancer Immunol Immunother

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“…4d and S4d ). Both these latter proteins are regulated by HIF-1α-dependent transcription and are involved in the promotion of the invasive phenotype [ 60 – 62 ]. Similarly, we found no significant variations in the expression of genes related to the EMT, such as cadherins, Twist, Snail , and Slug (Fig.…”

Section: Resultsmentioning

confidence: 99%

Pharmacological targeting of the mitochondrial calcium-dependent potassium channel KCa3.1 triggers cell death and reduces tumor growth and metastasis in vivo

et al. 2022

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Ion channels are non-conventional, druggable oncological targets. The intermediate-conductance calcium-dependent potassium channel (KCa3.1) is highly expressed in the plasma membrane and in the inner mitochondrial membrane (mitoKCa3.1) of various cancer cell lines. The role mitoKCa3.1 plays in cancer cells is still undefined. Here we report the synthesis and characterization of two mitochondria-targeted novel derivatives of a high-affinity KCa3.1 antagonist, TRAM-34, which retain the ability to block channel activity. The effects of these drugs were tested in melanoma, pancreatic ductal adenocarcinoma and breast cancer lines, as well as in vivo in two orthotopic models. We show that the mitochondria-targeted TRAM-34 derivatives induce release of mitochondrial reactive oxygen species, rapid depolarization of the mitochondrial membrane, fragmentation of the mitochondrial network. They trigger cancer cell death with an EC50 in the µM range, depending on channel expression. In contrast, inhibition of the plasma membrane KCa3.1 by membrane-impermeant Maurotoxin is without effect, indicating a specific role of mitoKCa3.1 in determining cell fate. At sub-lethal concentrations, pharmacological targeting of mitoKCa3.1 significantly reduced cancer cell migration by enhancing production of mitochondrial reactive oxygen species and nuclear factor-κB (NF-κB) activation, and by downregulating expression of Bcl-2 Nineteen kD-Interacting Protein (BNIP-3) and of Rho GTPase CDC-42. This signaling cascade finally leads to cytoskeletal reorganization and impaired migration. Overexpression of BNIP-3 or pharmacological modulation of NF-κB and CDC-42 prevented the migration-reducing effect of mitoTRAM-34. In orthotopic models of melanoma and pancreatic ductal adenocarcinoma, the tumors at sacrifice were 60% smaller in treated versus untreated animals. Metastasis of melanoma cells to lymph nodes was also drastically reduced. No signs of toxicity were observed. In summary, our results identify mitochondrial KCa3.1 as an unexpected player in cancer cell migration and show that its pharmacological targeting is efficient against both tumor growth and metastatic spread in vivo.

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“…LOX and the LOX family members (LOXL 1-4) are up-regulated in several melanoma cell lines while their down-regulation or inhibition reduces the invasion of melanoma cells [28,90]. While undetectable in melanocytes and primary melanoma cells, LOX upregulation was described in metastatic BLM cells and in the vertical growth phase of the WM793 melanoma cell line [28]. In our study, we investigated the LOX gene expression in relation to the EMT-related phenotype and differentiation state of melanoma cells for the first time.…”

Section: Discussionmentioning

confidence: 99%

“…Since LOX and the LOX family members (LOXL 1-4) are expressed and up-regulated in melanoma [28], we investigated LOX gene expression in our experimental models. LOX mRNA levels mirrored TGF-β1 gene expression and were significantly up-regulated in BLM 3D spheroids compared with 2D monolayers, while undetectable in A375 cells (Figure 6B).…”

Section: Tgf-β1 and Lox Gene Expressionmentioning

confidence: 99%

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Differentiation States of Phenotypic Transition of Melanoma Cells Are Revealed by 3D Cell Cultures

Fontana,

Sommariva,

Anselmi

et al. 2024

Cells

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Melanoma is characterized by high metastatic potential favored by the epithelial-to-mesenchymal transition (EMT), leading melanoma cells to exhibit a spectrum of typical EMT markers. This study aimed to analyze the expression of EMT markers in A375 and BLM melanoma cell lines cultured in 2D monolayers and 3D spheroids using morphological and molecular methods. The expression of EMT markers was strongly affected by 3D arrangement and revealed a hybrid phenotype for the two cell lines. Indeed, although E-cadherin was almost undetectable in both A375 and BLM cells, cortical actin was detected in A375 2D monolayers and 3D spheroids and was strongly expressed in BLM 3D spheroids. The mesenchymal marker N-cadherin was significantly up-regulated in A375 3D spheroids while undetectable in BLM cells, but vimentin was similarly expressed in both cell lines at the gene and protein levels. This pattern suggests that A375 cells exhibit a more undifferentiated/mesenchymal phenotype, while BLM cells have more melanocytic/differentiated characteristics. Accordingly, the Zeb1 and 2, Slug, Snail and Twist gene expression analyses showed that they were differentially expressed in 2D monolayers compared to 3D spheroids, supporting this view. Furthermore, A375 cells are characterized by a greater invasive potential, strongly influenced by 3D arrangement, compared to the BLM cell line, as evaluated by SDS-zymography and TIMPs gene expression analysis. Finally, TGF-β1, a master controller of EMT, and lysyl oxidase (LOX), involved in melanoma progression, were strongly up-regulated by 3D arrangement in the metastatic BLM cells alone, likely playing a role in the metastatic phases of melanoma progression. Overall, these findings suggest that A375 and BLM cells possess a hybrid/intermediate phenotype in relation to the expression of EMT markers. The former is characterized by a more mesenchymal/undifferentiated phenotype, while the latter shows a more melanocytic/differentiated phenotype. Our results contribute to the characterization of the role of EMT in melanoma cells and confirm that a 3D cell culture model could provide deeper insight into our understanding of the biology of melanoma.

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Divergent roles of lysyl oxidase family members in ornithine decarboxylase- and RAS-transformed mouse fibroblasts and human melanoma cells

Cited by 5 publications

References 92 publications

Lysyl oxidases: linking structures and immunity in the tumor microenvironment

Lysyl oxidases: linking structures and immunity in the tumor microenvironment

Pharmacological targeting of the mitochondrial calcium-dependent potassium channel KCa3.1 triggers cell death and reduces tumor growth and metastasis in vivo

Differentiation States of Phenotypic Transition of Melanoma Cells Are Revealed by 3D Cell Cultures

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