Regulation of MMP-1 expression in response to hypoxia is dependent on the intracellular redox status of metastatic bladder cancer cells

Shin, Dong-Woo; Dier, Usawadee; Melendez, J. Andrés; Hempel, Nadine

doi:10.1016/j.bbadis.2015.09.001

Cited by 63 publications

(44 citation statements)

References 59 publications

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“…In this regard, MMP-1 expression has been reported to contribute to the progression of Head and neck squamous cell carcinomas (HNSCC) and the suggest metastatic phenotype of human breast and colorectal cancers, among others (119)(120)(121). Interestingly, MMP-1/protease-activated receptor-1 (PAR1) signaling axis has been implicated in tumor angiogenesis and intravasation of carcinoma cells by inducing vascular permeability (122), as well as, hypoxia-regulated MMP-1 expression in metastatic bladder cancer cells, which could be associated to a reactive oxygen species (ROS)-related regulation of the spheroid metastatic phenotype and cell spread (123). The increased expression of MMP-1 in human chondrosarcoma is an important prognostic factor and its function in the spread of tumor cells has been evaluated by silencing assays in which cancer metastasis is impaired but local tumor growth and angiogenesis are enhanced (124).…”

Section: Soluble Mmps In Cancer Angiogenesismentioning

confidence: 99%

Role of Matrix Metalloproteinases in Angiogenesis and Cancer

et al. 2019

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During angiogenesis, new vessels emerge from existing endothelial lined vessels to promote the degradation of the vascular basement membrane and remodel the extracellular matrix (ECM), followed by endothelial cell migration, and proliferation and the new generation of matrix components. Matrix metalloproteinases (MMPs) participate in the disruption, tumor neovascularization, and subsequent metastasis while tissue inhibitors of metalloproteinases (TIMPs) downregulate the activity of these MMPs. Then, the angiogenic response can be directly or indirectly mediated by MMPs through the modulation of the balance between pro-and anti-angiogenic factors. This review analyzes recent knowledge on MMPs and their participation in angiogenesis.

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Section: Soluble Mmps In Cancer Angiogenesismentioning

confidence: 99%

Role of Matrix Metalloproteinases in Angiogenesis and Cancer

et al. 2019

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“…This result can be explained by the enhanced metastasis to the liver and colon in SCID mice injected with NCLX KO HCT116 cells. Indeed, we were able to show that the increased invasive properties of NCLX KO CRC cells were associated with increased MMP1, MMP2, and MMP9 activities, mRNA and protein levels, which are known to be regulated by HIF1α (Ben-Yosef et al, 2002;Choudhry and Harris, 2018;Muñoz-Nájar et al, 2006;Shin et al, 2015;Tsai et al, 2016). We showed that NCLX KO CRC cells are chemoresistant to treatment by 5-FU, with both proliferation and migration of NCLX KO CRC cells not significantly altered by 5-FU treatment.…”

Section: Discussionmentioning

confidence: 72%

Colorectal adenocarcinomas downregulate the mitochondrial Na⁺/Ca²⁺exchanger NCLX to drive metastatic spread

Pathak

Guéguinou

Walter

et al. 2020

Preprint

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Highlights• The expression of NCLX is decreased in colorectal tumors and is associated with advanced-stage disease in patients. • NCLX plays a dichotomous role in colorectal tumor growth and metastasis.• NCLX downregulation causes mitophagy and reduced colorectal cancer tumor growth.• NCLX downregulation induces stemness, chemoresistance and metastasis through mtCa 2+ /ROS/HIF1α signaling axis. Graphical Abstract SummaryDespite the established role of mitochondria in tumorigenesis, the molecular mechanisms by which mitochondrial Ca 2+ (mtCa 2+ ) signaling regulates tumor growth and metastasis remain unknown. The crucial role of mtCa 2+ in tumorigenesis is highlighted by the altered expression of proteins mediating mtCa 2+ uptake and extrusion in cancer cells. Here, we demonstrate that expression of the mitochondrial Na + /Ca 2+ exchanger NCLX (SLC8B1) is decreased in colorectal tumors and is associated with advanced-stage disease in patients. We reveal that downregulation of NCLX leads to mtCa 2+ overload, mitochondrial depolarization, mitophagy, and reduced tumor size. Concomitantly, NCLX downregulation drives metastatic spread, chemoresistance, the expression of epithelial-to-mesenchymal transition (EMT), hypoxia, and stem cell pathways. Mechanistically, mtCa 2+ overload leads to an increase in mitochondrial reactive oxygen species (mtROS) which activates HIF1α signaling supporting the metastatic behavior of tumor cells lacking NCLX. Our results reveal that loss of NCLX expression is a novel driver of metastatic progression, indicating that control of mtCa 2+ levels is a novel therapeutic approach in metastatic colorectal cancer. SignificanceMitochondrial Ca 2+ (mtCa 2+ ) homeostasis is essential for cellular metabolism and growth and plays a critical role in cancer progression. mtCa 2+ uptake is mediated by an inner membrane protein complex containing the mitochondrial Ca 2+ uniporter (MCU). mtCa 2+ uptake by the MCU is followed by a ∼100-fold slower mtCa 2+ extrusion mediated by the inner mitochondrial membrane ion transporter, the mitochondrial Na + /Ca 2+ exchanger NCLX. Because NCLX is a slower transporter than the MCU, it is a crucial rate-limiting factor of mtCa 2+ homeostasis that cannot easily be compensated by another Ca 2+ transport mechanism. This represents the first study investigating the role of NCLX in tumorigenesis and metastasis. We demonstrate for the first time that colorectal cancers exhibit loss of NCLX expression and that this is associated with advancedstage disease. Intriguingly, decreased NCLX function has a dichotomous role in colorectal cancer. Thus, we reveal that NCLX loss leads to reduced primary tumor growth and overall tumor burden in vivo. Yet, the consequential increases in mtCa 2+ elicit pro-survival, hypoxic and gene transcription pathways that enhance metastatic progression. This dichotomy is a well-established feature of chemoresistant and recurrent tumor cells including cancer stem cells. Moreover, the downstream changes elicited by NCLX loss are reminiscent of mesenchym...

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“…11 Therefore, there is an interest in the de- 6,40,41 Although the function of the angiopoietinlike 4 C-terminal fragment has not yet been clarified, previous studies have shown that hypoxia and L-mimosine can modulate the proteolytic activity. 26,42,43 In particular, the reduction of the plasminogen activation capacity was reported in fibroblasts of the gingiva and the periodontal ligament. 26 Hypoxia and hypoxia mimetic agents such as L-mimosine can therefore not only increase angiopoietin-like 4 expression but may also induce proteolytic processing in the periodontium.…”

Section: Discussionmentioning

confidence: 98%

“…For instance, angiopoietin‐like 4 is proteolytically processed and releases the C‐terminal fibrinogen‐like domain after proteolytic cleavage . Although the function of the angiopoietin‐like 4 C‐terminal fragment has not yet been clarified, previous studies have shown that hypoxia and L‐mimosine can modulate the proteolytic activity . In particular, the reduction of the plasminogen activation capacity was reported in fibroblasts of the gingiva and the periodontal ligament .…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin‐like 4 production upon treatment with hypoxia and L‐mimosine in periodontal fibroblasts

Janjić

Schellner

Engenhart

et al. 2019

J of Periodontal Research

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Background and objective A key factor in the modulation of angiogenesis as well as in bone resorption is angiopoietin‐like 4. However, the role of angiopoietin‐like 4 in periodontal tissue is unknown. Here, we hypothesized that hypoxia and the hypoxia mimetic agent L‐mimosine can induce the production of angiopoietin‐like 4 in periodontal fibroblasts. Methods Human periodontal ligament fibroblasts (PDLF) were cultured in monolayer and spheroid cultures. The cultures were incubated in the presence of hypoxia or L‐mimosine. Angiopoietin‐like 4 mRNA and protein levels were measured by qPCR and ELISA, respectively. Also, the impact of Lipopolysaccharides of E. coli and P. gingivalis, interleukin (IL)‐1β and tumor necrosis factor (TNF)α was evaluated. Furthermore, we tested dependency on hypoxia‐inducible factor (HIF)‐1 activity by Western blotting for HIF‐1 and inhibitor studies with echinomycin. Potential autocrine effects were assessed by exposure of PDLF to recombinant angiopoietin‐like 4 in full length, C‐terminal and N‐terminal fragments. The impact on viability, DNA synthesis, alkaline phosphatase, and matrix mineralization was evaluated. Results Both hypoxia and L‐mimosine elevated angiopoietin‐like 4 mRNA and protein levels in monolayer cultures of PDLF. HIF‐1 was elevated after both hypoxia and L‐mimosine treatment. LPS, IL‐1β, and TNFα did not modulate angiopoietin‐like 4 levels significantly. Addition of echinomycin in the cultures inhibited the production of angiopoietin‐like 4. In spheroid cultures of PDLF, the increase did not reach the level of significance at mRNA and protein levels. Angiopoietin‐like 4 in full length, C‐terminal, and N‐terminal fragments did not modulate viability, DNA synthesis, alkaline phosphatase, and matrix mineralization. Conclusion Overall, we found that hypoxia and the hypoxia mimetic agent L‐mimosine can stimulate angiopoietin‐like 4 production in monolayer cultures of PDLF. This increase depends on HIF‐1 activity. Future studies will reveal how the modulation of angiopoietin‐like 4 in the periodontium contributes to periodontal disease and regeneration.

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Regulation of MMP-1 expression in response to hypoxia is dependent on the intracellular redox status of metastatic bladder cancer cells

Cited by 63 publications

References 59 publications

Role of Matrix Metalloproteinases in Angiogenesis and Cancer

Role of Matrix Metalloproteinases in Angiogenesis and Cancer

Colorectal adenocarcinomas downregulate the mitochondrial Na⁺/Ca²⁺exchanger NCLX to drive metastatic spread

Angiopoietin‐like 4 production upon treatment with hypoxia and L‐mimosine in periodontal fibroblasts

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Regulation of MMP-1 expression in response to hypoxia is dependent on the intracellular redox status of metastatic bladder cancer cells

Cited by 63 publications

References 59 publications

Role of Matrix Metalloproteinases in Angiogenesis and Cancer

Role of Matrix Metalloproteinases in Angiogenesis and Cancer

Colorectal adenocarcinomas downregulate the mitochondrial Na+/Ca2+exchanger NCLX to drive metastatic spread

Angiopoietin‐like 4 production upon treatment with hypoxia and L‐mimosine in periodontal fibroblasts

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Colorectal adenocarcinomas downregulate the mitochondrial Na⁺/Ca²⁺exchanger NCLX to drive metastatic spread