Lysyl oxidase: a potential target for cancer therapy

Siddikuzzaman,; Grace, V. M. Berlin; Guruvayoorappan, Chandrasekharan

doi:10.1007/s10787-010-0073-1

Cited by 46 publications

(33 citation statements)

References 168 publications

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“…Buxton, (2010) recently proposed that secreted sNDPK-B regulates growth and development of metastases by stimulating angiogenesis and may facilitate intravasation, migration and extravasation early in the metastatic process. Estrogen and its receptors play an important role in the activation and expression of Nm23-H1 and down regulation of metastasis promoter genes such as WAVE3 (an actin-polymerization gene), Lysyl oxidase (LOX) and Merm1/Wbscr22 has been reported to inhibit invasion and metastasis of cancer (Lin et al, 2004;Sossey-Alaoui et al, 2007;Nakazawa et al, 2011;Siddikuzzaman et al, 2011). T-cell lymphoma invasion and metastasis 1 (Tiam1), an important protein binds with NDPK-A and inhibits Tiam1 activity specific for Rac1 and therefore interfere with Rac1-mediated actin polymerization and lamellipodia formation, which are essential for cell adhesion and migration (Otsuki et al, 2001;Raftopoulou, and Hall 2004).…”

Section: 3539 Targeting Tumor Metastasis By Regulating Nm23 Gene Expmentioning

confidence: 99%

Targeting Tumor Metastasis by Regulating Nm23 Gene Expression

Prabhu

Siddikuzzaman²,

Grace³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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The Nm23 gene is a metastatic suppressor identified in a melanoma cell line and expressed in different tumors where their levels of expression are associated with reduced or increased metastatic potential. Nm23 is one of the over 20 metastasis suppressor genes (MSGs) confirmed in vivo. It is highly conserved from yeast to human, implying a critical developmental function. Tumors with alteration of the p53 gene and reduced expression of the Nm23 gene are more prone to metastasis. Nm23-H1 has 3'-5' exonuclease activity. This review focuses on the role of Nm23 in cancer progression and also a potential novel target for cancer therapy.

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Section: 3539 Targeting Tumor Metastasis By Regulating Nm23 Gene Expmentioning

confidence: 99%

Targeting Tumor Metastasis by Regulating Nm23 Gene Expression

Prabhu

Siddikuzzaman²,

Grace³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…By determining BrdU incorporation and PCNA expression, we showed in our in vitro study that Cu chelation led to a dramatic inhibition of PASMC proliferation, while knockdown of CTR1 with siRNA also resulted in attenuation of PASMC proliferation (and migration) during hypoxia. Furthermore, inhibition of LOX has been proposed to treat hypertensive and fibrotic disorders [52], [53] and metastatic cancers [54]. In PASMC cultured in hypoxia, inhibition of LOX activity with βAPN also significantly attenuated proliferation indicating that increased Cu-dependent LOX activity is involved in stimulating PASMC proliferation.…”

Section: Discussionmentioning

confidence: 99%

Upregulated Copper Transporters in Hypoxia-Induced Pulmonary Hypertension

et al. 2014

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Pulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu) plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX), a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2) also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC). In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α) with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness.

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“…As mentioned earlier, LOX is secreted by cancer cells to create pre-metastatic niches by stimulating collagen cross-linking and fibronectin synthesis [25,26]. Adaptation to hypoxia is a driving force for tumor progression whereby hypoxia stimulates the hypoxia-inducible factor 1α (HIF-1α)-mediated LOX expression [27,28].…”

Section: Copper Proteins Involved In Diverse Aspects Of Cancermentioning

confidence: 99%

Roles of Copper-Binding Proteins in Breast Cancer

Blockhuys

Wittung-Stafshede

2017

IJMS

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Copper ions are needed in several steps of cancer progression. However, the underlying mechanisms, and involved copper-binding proteins, are mainly elusive. Since most copper ions in the body (in and outside cells) are protein-bound, it is important to investigate what copper-binding proteins participate and, for these, how they are loaded with copper by copper transport proteins. Mechanistic information for how some copper-binding proteins, such as extracellular lysyl oxidase (LOX), play roles in cancer have been elucidated but there is still much to learn from a biophysical molecular viewpoint. Here we provide a summary of copper-binding proteins and discuss ones reported to have roles in cancer. We specifically focus on how copper-binding proteins such as mediator of cell motility 1 (MEMO1), LOX, LOX-like proteins, and secreted protein acidic and rich in cysteine (SPARC) modulate breast cancer from molecular and clinical aspects. Because of the importance of copper for invasion/migration processes, which are key components of cancer metastasis, further insights into the actions of copper-binding proteins may provide new targets to combat cancer.

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Lysyl oxidase: a potential target for cancer therapy

Cited by 46 publications

References 168 publications

Targeting Tumor Metastasis by Regulating Nm23 Gene Expression

Targeting Tumor Metastasis by Regulating Nm23 Gene Expression

Upregulated Copper Transporters in Hypoxia-Induced Pulmonary Hypertension

Roles of Copper-Binding Proteins in Breast Cancer

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