Uncovering the role of nuclear Lysyl oxidase (LOX) in advanced high grade serous ovarian cancer

Donato, Marta De; Petrillo, Marco; Martinelli, Elisa; Filippetti, Flavia; Zannoni, Gian Franco; Scambia, Giovanni; Gallo, Daniela

doi:10.1016/j.ygyno.2017.05.001

Cited by 30 publications

(26 citation statements)

References 36 publications

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“…LOX, overexpressed in advanced MRT PDX (gene and protein) and in the sorted ALDH1+ cell fraction was further shown to localize to subpopulations of cells in archived primary MRT samples and to MRT G401 cell line. Importantly, the increased nuclear LOX expression in advanced PDX is consistent with emerging evidence showing that high nuclear LOX expression is in correlation with tumor aggressiveness and poor prognosis ( De Donato et al., 2017 , Liu et al., 2017 ). Inhibition of LOX showed effects on in vitro proliferation, migration, and invasiveness of MRT cells derived from progressive PDX, G401 cell line, and G401 xenografts.…”

Section: Discussionsupporting

confidence: 86%

In Vivo Expansion of Cancer Stemness Affords Novel Cancer Stem Cell Targets: Malignant Rhabdoid Tumor as an Example

et al. 2018

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SummaryCancer stem cell (CSC) identification relies on transplantation assays of cell subpopulations sorted from fresh tumor samples. Here, we attempt to bypass limitations of abundant tumor source and predetermined immune selection by in vivo propagating patient-derived xenografts (PDX) from human malignant rhabdoid tumor (MRT), a rare and lethal pediatric neoplasm, to an advanced state in which most cells behave as CSCs. Stemness is then probed by comparative transcriptomics of serial PDXs generating a gene signature of epithelial to mesenchymal transition, invasion/motility, metastasis, and self-renewal, pinpointing putative MRT CSC markers. The relevance of these putative CSC molecules is analyzed by sorting tumorigenic fractions from early-passaged PDX according to one such molecule, deciphering expression in archived primary tumors, and testing the effects of CSC molecule inhibition on MRT growth. Using this platform, we identify ALDH1 and lysyl oxidase (LOX) as relevant targets and provide a larger framework for target and drug discovery in rare pediatric cancers.

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Section: Discussionsupporting

confidence: 86%

In Vivo Expansion of Cancer Stemness Affords Novel Cancer Stem Cell Targets: Malignant Rhabdoid Tumor as an Example

et al. 2018

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“…Therefore, PCN rather than the cancerous cell itself triggers carcinogenesis. Lysyl oxidase functions as a tumor promoter in advanced high-grade serous ovarian cancer and in facilitating the cascade of events leading to metastasis [288]. Increased lysyl oxidase expression levels in laryngeal cancer are associated with lymph node and distant metastasis and poor patient outcome [289] and inhibition of lysyl oxidase decreases or prevents fibrosis, metastasis, cell migration and motility [273][274][275][276][277][278][279][280][281][282][283][284][285].…”

Section: Extracellular Matrix and Lysyl Oxidasementioning

confidence: 99%

Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation

Brücher

Jamall

2019

4open

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Fibroblasts are actively involved in the creation of the stroma and the extracellular matrix which are important for cell adhesion, cell–cell communication, and tissue metabolism. The role of fibrosis in carcinogenesis can be examined by analogy to tissues of various cancers. The orchestration of letters in the interplay of manifold components with signaling and crosstalk is incompletely understood but available evidence suggests a hitherto underappreciated role for fibrosis in carcinogenesis. Complex signaling and crosstalk by pathogenic stimuli evoke persistent subclinical inflammation, which in turn, results in a cascade of different cell types, ubiquitous proteins and their corresponding enzymes, cytokine releases, and multiple signaling pathways promoting the onset of fibrosis. There is considerable evidence that the body's attempt to resolve such a modified extracellular environment leads to further disruption of homeostasis and the genesis of the precancerous niche as part of the six-step process that describes carcinogenesis. The precancerous niche is formed and can be understood to develop as a result of (1) pathogenic stimulus, (2) chronic inflammation, and (3) fibrosis with alterations of the extracellular matrix, stromal rigidity, and mechano-transduction. This is why carcinogenesis is not just a process of aberrant cell growth with damaged genetic material but the role of the PCN in its entirety reveals how carcinogenesis can occur without invoking the need for somatic mutations.

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“…LOX is an extracellular enzyme that catalyzes the crosslink formation in collagen and elastin fibrils, however, LOX was reported to be also present in the nuclear compartments [13]. The nuclear localization of LOX has been further reported in several different tumor tissues, including clear cell renal cell carcinoma, rectal carcinoma, and high-grade serous ovarian carcinoma [27][28][29]. In our findings, both LOX and LOX-v2 showed significant amine oxidase activity toward histone H2A in in vitro peroxidase-coupled fluorometric assays, however, only LOX-v2 displayed cellular localization in the nucleus where histone proteins are located.…”

Section: Discussionmentioning

confidence: 99%

Lysyl oxidase-variant 2 functions as an amine oxidase toward histone H2A

Li¹,

Sharma-Bhandari²,

Kim³

2020

J Biomed Transl Res

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Lysyl oxidase-variant 2 (LOX-v2) is a novel variant of lysyl oxidase (LOX) that functions as an amine oxidase for the formation of lysine-mediated crosslinks found in collagen and elastin fibrils. In addition to the amine oxidase activity in the extracellular matrix, several novel functions, such as tumor suppression, tumor progression, chemotaxis, cellular senescence, and modification of histones, have been assigned to LOX. In recent years, it has been reported that LOX is also present in nuclear locations, suggesting a novel functional role of LOX in the nucleus. To test the amine oxidase activity of LOX and LOX-v2 to nuclear histone proteins, we expressed and purified LOX and LOX-v2 as recombinant forms and then assessed the amine oxidase activity toward histone H2A in in vitro peroxidase-coupled fluorometric assays. Both LOX and LOX-v2 proteins showed significant levels of amine oxidase activity toward histone H2A in a β-aminopropionitrile-inhibitable manner. In immunofluorescence staining after ectopic expression in cultured cells, LOX was observed in the perinuclear, cytoplasmic, and extracellular areas, whereas LOX-v2 was predominantly detected in the nucleoplasm with a punctuate pattern. These findings suggest that LOX-v2 may play a novel functional role in the nucleus through the amine oxidase activity to the nuclear histone proteins. Elucidation of the specific functional roles of LOX-v2, such as substrate specificity toward different types of nuclear proteins and detailed analysis on subnuclear localization, will provide a significant clue in understanding the diverse functional roles currently assigned to a single enzyme, LOX.

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Uncovering the role of nuclear Lysyl oxidase (LOX) in advanced high grade serous ovarian cancer

Cited by 30 publications

References 36 publications

In Vivo Expansion of Cancer Stemness Affords Novel Cancer Stem Cell Targets: Malignant Rhabdoid Tumor as an Example

In Vivo Expansion of Cancer Stemness Affords Novel Cancer Stem Cell Targets: Malignant Rhabdoid Tumor as an Example

Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation

Lysyl oxidase-variant 2 functions as an amine oxidase toward histone H2A

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