Targeting the Warburg Effect That Arises in Tumor Cells Expressing Membrane Type-1 Matrix Metalloproteinase

Cancer metastasis is intricately orchestrated by both cancer and normal cells, such as endothelial cells and macrophages. Monocytes/macrophages, which are often co-opted by cancer cells and promote tumor malignancy, acquire more than half of their energy from glycolysis even during normoxic conditions. This glycolytic activity is maintained during normoxia by the functions of hypoxia inducible factor 1 (HIF-1) and its activator APBA3. The mechanism by which APBA3 inhibition partially suppresses macrophage function and affects cancer metastasis is of interest in view of avoidance of the adverse effects of complete suppression of macrophage function during therapy. Here, we report that APBA3-deficient mice show reduced metastasis, with no apparent effect on primary tumor growth. APBA3 deficiency in inflammatory monocytes, which strongly express the chemokine receptor CCR2 and are recruited toward chemokine CCL2 from metastatic sites, hampers glycolysis-dependent chemotaxis of cells toward metastatic sites and inhibits VEGFA expression, similar to the effects observed with HIF-1 deficiency. Host APBA3 induces VEGFA-mediated E-selectin expression in the endothelial cells of target organs, thereby promoting extravasation of cancer cells and micrometastasis formation. Administration of E-selectin-neutralizing antibody also abolished host APBA3-mediated metastatic formation. Thus, targeting APBA3 is useful for controlling metastatic niche formation by inflammatory monocytes.APBA3/Mint3 | macrophage | metastasis C ancer metastasis comprises multiple processes of neoplastic progression, termed the "invasion-metastasis cascade" (1, 2). Thousands of circulating tumor cells (CTCs) can be released from invasive primary tumors; however, most patients develop only a few metastases, suggesting that metastatic initiation processes (such as extravasation and colonization at distant organs) are quite inefficient but key for controlling metastatic cancer diseases. Unlike at primary sites, single or small groups of disseminated CTCs encounter large numbers of normal cells in their new environments, which determines their survival and metastatic efficiency, as shown by studies with genetically engineered mouse models (3-5).Macrophages are myeloid cells that are co-opted essentially to foster tumor progression and metastasis. The functions of tumorassociated macrophages include angiogenesis, suppression of antitumor immune responses, chemoresistance, and metastasis; these are considered novel targets for cancer therapy (6-10). Monocytes (i.e., macrophage precursors) are characterized by the surface molecules CD11b and CD115, and comprise at least two subsets: Gr-1 + (Ly-6C high )CCR2 + CX3CR1 low inflammatory monocytes (IMs) and Gr-1 low (Ly-6C low )CCR2 low CX3CR1 high resident monocytes (RMs) (11). Their recruitment from the bone marrow (BM) to peripheral tissues is mediated mainly by chemokine-chemokine receptor complexes such as the CCL2/CCR2 system (12, 13). Even in metastatic cascades, the CCL2-CCR2 axis is a key pathway for IM ...

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“…ATP levels were normalized to total protein concentration, as determined using a Bradford assay kit (Bio-Rad) as previously described (57).…”

Section: Methodsmentioning

confidence: 99%

Control of metastatic niche formation by targeting APBA3/Mint3 in inflammatory monocytes

Hara

Nakaoka

Hayashi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…This increased glycolysis rate not only supplies energy but also generates a variety of glucose metabolites that are used as building blocks for the cellular constituents that must be created to support cell division (13). We have recently reported that the suppression of HIF-1␣ by FIH-1 is abrogated in malignant tumor cells because of FIH-1 inactivation (14). However, other mechanisms of HIF-1␣ inactivation that are mediated by PHDs remain active in such cells.…”

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confidence: 97%

“…Cooperation between the two FIH-1-binding proteins MT1-MMP cytoplasmic tail and Mint3 thus efficiently recruits cytoplasmic FIH-1 to the membrane, where FIH-1 is then inhibited by Mint3. This MT1-MMP/Mint3-dependent inactivation of FIH-1 occurs in both macrophages and tumor cells (14,16,21). Depletion of MT1-MMP in macrophages restores FIH-1-mediated suppression of HIF-1␣ and thereby reduces ATP production by glycolysis to nearly 40% of the level observed in wild-type cells (21).…”

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“…Although HIF-1␣ protein levels can be suppressed by PHD activity during normoxia, the residual HIF-1␣ protein is sufficient to promote the expression of target genes after release of HIF-1␣ from suppression by FIH-1. Indeed, knockdown of FIH-1 expression in nontransformed cells significantly activates HIF-1 activity, enhances the expression of HIF-1 target genes, and boosts the glycolytic activity of the cells (14).…”

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Hypoxia-Inducible Factor 1 Regulation through Cross Talk between mTOR and MT1-MMP

Sakamoto

Weng

Hara

et al. 2014

Molecular and Cellular Biology

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“…Interestingly, it has been reported recently that tumor cell lines expressing MT1-MMP (MMP-14), a membrane-type MMP, exhibit increased glycolytic activity and moreover, that transfection of this enzyme in MT1-MMP-negative tumor cells induces the Warburg effect by activating HIF-1␣ (26). Similarly, in our study we found that in addition to repressing oxygen consumption, MMP-1-transfected cells displayed a higher activation of HIF-1␣ importantly under normoxia and in hypoxic conditions.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase (MMP)-1 Induces Lung Alveolar Epithelial Cell Migration and Proliferation, Protects from Apoptosis, and Represses Mitochondrial Oxygen Consumption

Herrera

Cisneros

Maldonado

et al. 2013

Journal of Biological Chemistry

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Background:In IPF MMP-1 is up-regulated and expressed in alveolar epithelial cells. Result: Transfection of MMP-1 in MLE cells increased proliferation/migration, protected from apoptosis, repressed oxygen consumption ratio and ROS production, and stimulated HIF-1␣. Conclusion: MMP-1 inhibits mitochondrial function and contributes to a proliferative/migratory and anti-apoptotic phenotype. Significance: MMP-1 promotes the Warburg effect characterized by increased aerobic glycolysis and HIF-1␣ during normoxia.

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Targeting the Warburg Effect That Arises in Tumor Cells Expressing Membrane Type-1 Matrix Metalloproteinase

Cited by 71 publications

References 58 publications

Control of metastatic niche formation by targeting APBA3/Mint3 in inflammatory monocytes

Control of metastatic niche formation by targeting APBA3/Mint3 in inflammatory monocytes

Hypoxia-Inducible Factor 1 Regulation through Cross Talk between mTOR and MT1-MMP

Matrix Metalloproteinase (MMP)-1 Induces Lung Alveolar Epithelial Cell Migration and Proliferation, Protects from Apoptosis, and Represses Mitochondrial Oxygen Consumption

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