Silibinin Inhibits NSCLC Metastasis by Targeting the EGFR/LOX Pathway

Hou, Xiaoying; Du, Hongzhi; Quan, Xingping; Shi, Lei; Zhang, Qianqian; Wu, Yao; Liu, Yang; Xiao, Jing; Li, Yong; Lu, Ligong; Ai, Xun; Zhan, Meixiao; Yuan, Shengtao; Sun, Li

doi:10.3389/fphar.2018.00021

Cited by 37 publications

(23 citation statements)

References 54 publications

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“…Although LOX pro-peptide displays tumor suppressor activity [10], LOX family oxidases support metastasis [37]. In NSCLC, high LOX expression is associated with invasion and poor prognosis [38], and targeting the LOX pathway in tumor cells inhibits metastasis [39]. Similarly, high level of LOXL2 is associated with poor prognosis in NSCLC [40] and LOXL2 promotes the formation of a pre-metastatic niche [41].…”

Section: Discussionmentioning

confidence: 99%

LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity

Zeltz

Cox

Navab

et al. 2019

Cancers

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Integrin α11, a stromal collagen receptor, promotes tumor growth and metastasis of non-small cell lung cancer (NSCLC) and is associated with the regulation of collagen stiffness in the tumor stroma. We have previously reported that lysyl oxidase like-1 (LOXL1), a matrix cross-linking enzyme, is down-regulated in integrin α11-deficient mice. In the present study, we investigated the relationship between LOXL1 and integrin α11, and the role of LOXL1 in NSCLC tumorigenicity. Our results show that the expression of LOXL1 and integrin α11 was correlated in three lung adenocarcinoma patient datasets and that integrin α11 indeed regulated LOXL1 expression in stromal cells. Using cancer-associated fibroblast (CAF) with either a knockdown or overexpression of LOXL1, we demonstrated a role for LOXL1 in collagen matrix remodeling and collagen fiber alignment in vitro and in vivo in a NSCLC xenograft model. As a consequence of collagen reorganization in NSCLC tumor stroma, we showed that LOXL1 supported tumor growth and progression. Our findings demonstrate that stromal LOXL1, under regulation of integrin α11, is a determinant factor of NSCLC tumorigenesis and may be an interesting target in this disease.

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Section: Discussionmentioning

confidence: 99%

LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity

Zeltz

Cox

Navab

et al. 2019

Cancers

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“…Caveolae-compartmentalized and Ang II-induced signals involve metalloprotease ADAM17/tissue necrosis factor-α (TNF-α), converting the enzyme responsible for epidermal growth factor receptor (EGFR) transactivation, as analyzed in VSMC/ADAM17-deficienct mice [ 11 ]. The activated EGFR is known to regulate LOX expression via the PI3K/AKT, MEK/ERK and SAPK/JNK pathways, as observed in human non-small cell lung carcinoma cell lines and confirmed in vivo in an orthotopic metastasis mouse model and in human tumor tissue microarray analysis [ 12 ]. In turn, LOX regulation of EGFR also occurs, and was found, in primary and metastatic breast cancer cells, to be linked to the suppression of TGFβ1 signaling with the involvement of HTRA1, leading to increased expression of the EGF-like domain-containing MATN2 that traps EGFR at the cell surface, as part of its activation by EGF [ 13 ].…”

Section: Caveolae Compartmentalized Lox: Angiotensin II and Epidermentioning

confidence: 96%

Lysyl Oxidase (LOX): Functional Contributions to Signaling Pathways

Laczkó

Csiszár

2020

Biomolecules

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Cu-dependent lysyl oxidase (LOX) plays a catalytic activity-related, primary role in the assembly of the extracellular matrix (ECM), a dynamic structural and regulatory framework which is essential for cell fate, differentiation and communication during development, tissue maintenance and repair. LOX, additionally, plays both activity-dependent and independent extracellular, intracellular and nuclear roles that fulfill significant functions in normal tissues, and contribute to vascular, cardiac, pulmonary, dermal, placenta, diaphragm, kidney and pelvic floor disorders. LOX activities have also been recognized in glioblastoma, diabetic neovascularization, osteogenic differentiation, bone matrix formation, ligament remodeling, polycystic ovary syndrome, fetal membrane rupture and tumor progression and metastasis. In an inflammatory context, LOX plays a role in diminishing pluripotent mesenchymal cell pools which are relevant to the pathology of diabetes, osteoporosis and rheumatoid arthritis. Most of these conditions involve mechanisms with complex cell and tissue type-specific interactions of LOX with signaling pathways, not only as a regulatory target, but also as an active player, including LOX-mediated alterations of cell surface receptor functions and mutual regulatory activities within signaling loops. In this review, we aim to provide insight into the diverse ways in which LOX participates in signaling events, and explore the mechanistic details and functional significance of the regulatory and cross-regulatory interactions of LOX with the EGFR, PDGF, VEGF, TGF-β, mechano-transduction, inflammatory and steroid signaling pathways.

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“…As a transmembrane receptor tyrosine kinase, the overexpressed EGFR has been broadly discovered in NSCLC 19. The downstream signaling pathways participated in the mediation of tumor growth, invasion and metastasis could be stimulated by the activated EGFR 20. Incorporating onto the membranes, DHA played a role in regulating the functions of cellular membranes and the organization of lipid rafts, displacing EGFR from lipid rafts, which subsequently resulted in the suppression of the downstream signaling activities 21,22.…”

Section: Discussionmentioning

confidence: 99%

<p>Docosahexaenoic Acid Serving As Sensitizing Agents And Gefitinib Resistance Revertants In EGFR Targeting Treatment</p>

Ding¹,

Liu²,

Yan³

et al. 2019

OTT

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ObjectiveDue to the resistance of cancer cells, chemotherapy has been severely restricted. Docosahexaenoic acid (DHA) has been broadly identified as the chemo-sensitizing agent and revertant of multidrug resistance owing to its pleiotropic characteristics; however, it has not been well interpreted. The purpose of this research was to identify the anticancer role of DHA and its combination with the chemotherapeutic agent Gefitinib in non-small cell lung cancer (NSCLC).MethodsHuman chemo-sensitive NSCLC PC-9 cells and the Gefitinib-resistant counterpart PC-9/GR cells were adopted to assess the effects of the integrated DHA and Gefitinib treatments in vitro and vivo, for which the combination index (CI), apoptosis rate and the epithelial growth factor receptor (EGFR) pathway were analyzed.ResultsComparing with the control cells, the DHA-treated PC-9/GR cells triggered the increase of drug absorption and sensitivity, suggesting that the sensitivity of chemotherapeutic drug could be induced by DHA. Moreover, the elevation of phosphorylation levels of EGFR and the downstream extracellular signal-regulated kinase (ERK) in the cellular lysates were induced by the DHA+Gefitinib treatment. Additionally, the long-term Gefitinib stimulated PC-9 model revealed that DHA could revert the Gefitinib resistance.ConclusionThis is the first research that indicated the novel biochemical effect of DHA, which can help in overcoming the resistance of EGFR-TKI in NSCLC cells and broaden the horizon of the DHA supplementation during the NSCLC therapy.

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Silibinin Inhibits NSCLC Metastasis by Targeting the EGFR/LOX Pathway

Cited by 37 publications

References 54 publications

LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity

LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity

Lysyl Oxidase (LOX): Functional Contributions to Signaling Pathways

<p>Docosahexaenoic Acid Serving As Sensitizing Agents And Gefitinib Resistance Revertants In EGFR Targeting Treatment</p>

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