Modulation of Lysyl Oxidase by Dietary Copper in Rats

Rucker, Robert B.; Romero-Chapman, Nadia; Wong, Toniel; Lee, Jill; Steinberg, Francene M.; McGee, Carl; Clegg, Michael S.; Reiser, Karen M.; Kosonen, Taru; Uriu‐Hare, Janet Y.; Murphy, James J.; Keen, Carl L.

doi:10.1093/jn/126.1.51

Cited by 47 publications

(38 citation statements)

References 41 publications

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“…Severe Cu deficiency resulted in decreased crosslinking of connective tissue, consistent with decreased function of LO [39] . Enzyme activity levels were decreased in the skin of weanling rats fed with a copper deficient diet [40] . Exogenously added Cu has been shown to elevate LO activity and LO mRNA levels in cultured RFL6 cells [41] .…”

Section: Discussionmentioning

confidence: 96%

Bleomycin induces upregulation of lysyl oxidase in cultured human fetal lung fibroblasts

Chen

et al. 2010

Acta Pharmacol Sin

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Aim: To investigate the mechanism of bleomycin (BLM)-induced pulmonary fibrosis. Methods: Cultured human fetal lung fibroblast (HLF) cells were exposed to bleomycin (BLM) at 0-30 μg/mL for 24 h. Western blot analysis was used to detect lysyl oxidase (LO) protein expression. Real-time RT-PCR was used to detect LO mRNA level. LO catalytic activity was measured using diaminopentane as a substrate and Amplex red as a hydrogen peroxide probe. Copper (Cu) concentration was detected by flame atomic absorption spectrophotometry. Results: Exposure of HLF cells to BLM at 10 μg/mL and 30 μg/mL increased LO catalytic activity to 130% and 158% of the control in the conditioned media. The expression of LO mRNA was increased to 5.5-fold of the control in HLF cells exposure to BLM at 3 μg/mL. BLM at 3 μg/mL also increased the expression of 46 kDa preproLO, 50 kDa proLO and 32 kDa mature LO to 219%, 130%, and 135% of the control, respectively. The Cu concentrations in conditioned media of cultured HLF cells exposed to BLM (10 and 30 μg/mL) were increased significantly to 1.48 and 2.46-fold of the control, respectively. Conclusion: Bleomycin induces upregulation of LO in cultured human fetal lung fibroblasts, which may be the mechanism of bleomycininduced pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 96%

Bleomycin induces upregulation of lysyl oxidase in cultured human fetal lung fibroblasts

Chen

et al. 2010

Acta Pharmacol Sin

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“…Previous studies of Cu deficiency in rats (Robins et al 1985;Farquharson et al 1989) showed significant effects on bone collagen cross-links only after a prolonged and severe deficiency, which produced a major decrement in body-weight gain, amonst other deleterious effects. The current consensus, therefore, seems to be that, in laboratory rodents at least, Cu deficiency needs to be both prolonged and severe before the activity of the Cu-dependent enzyme, lysyl oxidase, is impaired sufficiently to cause any significant effects on mature bone collagen cross-linking (Rucker et al 1996).…”

Section: Discussionmentioning

confidence: 99%

Vitamin C and copper interactions in guinea-pigs and a study of collagen cross-links

Tsuchiya

Bates

1997

Br J Nutr

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While it is clear from these studies that high concentrations or intakes of ascorbate can reduce tissue concentrations of Cu in a variety of species, there is a less clear consensus and uniformity with respect to possible functional effects of ascorbate overload on Cudependent processes in viva Several early studies on aortic rupture in chicks (Starcher et al. 1964;Carlton & Henderson, 1965;Hill & Starcher, 1965) obtained strong evidence for a gross failure of elastin cross-linking, attributed to reduced activity of the key enzyme, lysyl oxidase, in birds that were exposed simultaneously to excessive dietary ascorbate, and to low dietary Cu levels. Studies in mammalian species, however, have not reproduced such a dramatic effect. Nevertheless, in view of the potential importance of this interaction, for human subjects who choose to take daily megadoses of ascorbic acid, there is a need for further studies in relevant animal models such as the guinea-pig, which like humans has an absolute requirement for dietary ascorbate, as well as for Cu. The possibility that high levels of circulating vitamin C may increase the likelihood of Fe acting pro-oxidatively, and thereby influence outcome, has been illustrated by recent studies of human pre-term infants (Silvers et al. 1994;Powers et al. 1995). Deleterious effects of high ascorbate intakes may thus involve more than one transition metal.Another separate but related question arises from the need for better biochemical tests for suboptimum v. optimum status, with respect to those functionally-critical processes which are dependent on specific micronutrients. Collagen cross-linking is such a process. A severe lack of Cu can impair the activity of the Cu-dependent enzyme lysyl oxidase, responsible for the initiation of cross-linking (Farquharson et al. 1989;Robins, 1994). Impairment of cross-linking may then result in loss of tensile strength. Lack of ascorbic acid is well known to affect the hydroxylation of collagen lysyl residues (Kivirikko & Myllyla, 1982;Yeowell et al. 1995), and this could, in theory, alter the pattern of collagen cross-links, by altering the ratio of deoxypyridinoline (derived from lysine) to pyridinoline (derived from hydroxylysine) (Robins, 1994).The dual purpose of the present study was: first to re-examine the interactions of ascorbate and Cu, by dietary modulation in young guinea-pigs, and second, to test the hypothesis that Cu and/or ascorbate status might alter the ratio of deoxypyridinoline collagen-derived cross-links in bone and in urine. MATERIALS AND METHODS Animals and dietsThe purified guinea-pig diet contained the following components (g/kg): sucrose 331, maize starch 50, ovalbumin 300, cellulose powder 150, maize oil 73, potassium acetate 25, choline chloride 2, magnesium oxide 5 , inositol2, salt mixture 60, vitamins (see later). The salt mixture was based on that of Greenfield et al. (1969), except that the CuS04 therein was omitted. It contained (g/kg): CaC03 205, CaHP04 325, Na2HP04 185, KC1 205, MgS04 70, MnS04 4-5, Fe-citrate...

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“…The catalytic activity of LOX is copper-dependent with the carboxyterminus requiring the presence of a tightly bound active copper (II) ion (30). Although copper availability does not directly affect synthesis, it does markedly influence its functional activity (31,32). Tetrathiomolybdate is a potent copper chelator and has demonstrated antiangiogenic, antifibrogenic, and anti-inflammatory actions in preclinical studies.…”

Section: Therapeutic Potential and Clinical Implications For Future Tmentioning

confidence: 99%

Lysyl Oxidase, a Targetable Secreted Molecule Involved in Cancer Metastasis

2016

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Secondary metastatic cancer remains the single biggest cause of mortality and morbidity across most solid tumors. In breast cancer, 100% of deaths are attributed to metastasis. At present, there are no "cures" for secondary metastatic cancer of any form and there is an urgent unmet clinical need to improve the tools available in our arsenal against this disease, both in terms of treatment, but also prevention. Recently, we showed that hypoxic induction of the extracellular matrix modifying enzyme lysyl oxidase (LOX) correlates with metastatic dissemination to the bone in estrogen receptor negative breast cancer and is essential for the formation of premetastatic osteolytic lesions. We showed that in models of breast cancer metastasis, targeting LOX, or its downstream effects, significantly inhibited premetastatic niche formation and the resulting metastatic burden, offering preclinical validation of this enzyme as a therapeutic target for metastatic breast cancer. Our work is the latest in an emerging body of work supporting the targeting of LOX and calls for greater efforts in developing therapeutics against this extracellular secreted factor in the prevention of cancer progression across multiple solid tumor types. Cancer Res; 76(2); 188-92. Ó2016 AACR. Cancer Metastasis and the Importance of the Cellular MicroenvironmentThe spread of primary tumors to nonadjacent unrelated organs has proven to be a complex and difficult problem for researchers to tackle. This is because metastasis is a systemic process involving not only primary tumor cells, but also contributions from a vast and diverse range of nonmalignant host cells at both primary and secondary sites over varying timescales.Over the last two decades, it has become increasingly apparent in the field of cancer research that the genetic aberrations once seen as the primary drivers of cancer initiation and metastasis, can account for only a subset of the necessary steps required for progression. Additional contributions from the tumor microenvironment, dictated by both the tumor cells themselves, but more importantly by resident nonmalignant cells, provide an enormous repertoire of both soluble and insoluble cues, which facilitate metastasis. The dissemination of an isolated (and often surgically resectable) primary tumor to full-blown metastatic disease is a complex and reciprocal process, and it is currently unclear whether tumor cells or the microenvironment drives progression or they act equally. The deposition and posttranslational modification, as well as remodeling of the local extracellular matrix (ECM) has been shown to be critically important in metastasis both at primary and secondary sites. Similarly, the secretomes of cancer cells (and recruited host cells) have also been shown to be key in controlling the recruitment and response of nonmalignant host cells within the primary tumor microenvironment generating both feed-forward and feed-back signaling loops.The idea that a tumor can modulate not only the behavior of local cells and the re...

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Modulation of Lysyl Oxidase by Dietary Copper in Rats

Cited by 47 publications

References 41 publications

Bleomycin induces upregulation of lysyl oxidase in cultured human fetal lung fibroblasts

Bleomycin induces upregulation of lysyl oxidase in cultured human fetal lung fibroblasts

Vitamin C and copper interactions in guinea-pigs and a study of collagen cross-links

Lysyl Oxidase, a Targetable Secreted Molecule Involved in Cancer Metastasis

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