CD26 protease inhibition improves functional response of unfractionated cord blood, bone marrow, and mobilized peripheral blood cells to CXCL12/SDF-1

Christopherson, Kent W.; Frank, Robin R.; Jagan, Sucheta; Paganessi, Laura A.; Gregory, Stephanie A.; Fung, Henry C.

doi:10.1016/j.exphem.2012.07.009

Cited by 11 publications

(10 citation statements)

References 28 publications

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“…DPP-4 catalytically regulates the activity of biopeptides by proteolytically cleaving a number of peptides, cytokines, and chemokines (12). C-X-C motif chemokine 12 (CXCL12), also known as stromal cell-derived factor 1 (SDF1), is a confirmed substrate of DPP-4 (13). CXCL12 binds to C-X-C receptor 4 (CXCR4) and CXCR7 and thus regulates tumor growth and metastasis (14).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Dipeptidyl Peptidase-4 Accelerates Epithelial–Mesenchymal Transition and Breast Cancer Metastasis via the CXCL12/CXCR4/mTOR Axis

et al. 2019

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Dipeptidyl peptidase (DPP)-4 is a multifunctional glycoprotein involved in various biological and pathologic processes. DPP-4 has been widely recognized as a therapeutic target for type 2 diabetes mellitus but is also implicated in the development of human malignancies. Here, we show that inhibition of DPP-4 accelerates breast cancer metastasis via induction of CXCL12/CXCR4, which activates mTOR to promote epithelial-mesenchymal transition (EMT). In cultured cells, DPP-4 knockdown induced EMT and cell migration. Treatment with the DPP-4 inhibitor KR62436 (KR) promoted primary tumor growth and lung metastasis in a 4T1 tumor allograft mouse model; DPP-4 knockdown in 4T1 cells displayed similar phenotypes in vivo and in vitro. KR treatment enhanced the levels of CXCL12/CXCR4 and phosphorylated mTOR, which were associated with the induction of EMT in metastatic cancer cells. KR-induced EMT in cancer cells was inhibited by treatment with the CXCR4 inhibitor AMD3100 or the mTOR inhibitor rapamycin, and AMD3100 suppressed KR-induced metastasis in vivo. Our findings suggest that DPP-4 plays a significant role in cancer biology and that inhibition of DPP-4 promotes cancer metastasis via induction of the CXCL12/CXCR4/mTOR/EMT axis.Significance: These findings reveal that inhibition of DPP-4 increases the metastatic potential of breast cancer. This is especially important given the potential use of DPP-4 inhibition as a therapeutic strategy for type 2 diabetes.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Dipeptidyl Peptidase-4 Accelerates Epithelial–Mesenchymal Transition and Breast Cancer Metastasis via the CXCL12/CXCR4/mTOR Axis

et al. 2019

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“…These findings were further supported by the results suggesting that absence of negative regulation through DPP4 cleavage may be beneficial for immature megakaryocyte progenitors, although the mechanism remains to be determined [21]. DPP4 is expressed on mononuclear blood cells (MNCs) from cord blood, bone marrow, and mobilized peripheral blood, and inhibition of endogenous DPP4 using diprotin A (a tri-peptide inhibitor of DPP4 activity) enhanced the migration of MNCs to CXCL12 from all three cell sources [22 ▪ ]. The modulation of the CXCL12/CXCR4 axis via DPP4 for recruitment and homing of bone-marrow-derived stem cells is not limited to HSCs and hematopoietic cell transplantation.…”

Section: Dipeptidyl Peptidase 4 In Hematopoiesis and Cord Blood Transmentioning

confidence: 93%

“…The modulation of the CXCL12/CXCR4 axis via DPP4 for recruitment and homing of bone-marrow-derived stem cells is not limited to HSCs and hematopoietic cell transplantation. DPP4 has been shown to be necessary for G-CSF-induced mobilization [16,17,23], and inhibition of DPP4 has been shown to increase the transplant efficiency [15,19,24] and homing of stem cells to bone marrow regardless of how the stem cells were mobilized [22 ▪ ]. …”

Section: Dipeptidyl Peptidase 4 In Hematopoiesis and Cord Blood Transmentioning

confidence: 99%

The role of dipeptidyl peptidase 4 in hematopoiesis and transplantation

O’Leary¹,

Ou²,

Broxmeyer³

2013

Current Opinion in Hematology

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Purpose of review Dipeptidyl peptidase 4 (DPP4, CD26] is a protease that cleaves selected amino acids at the N-terminal penultimate position and has the potential to alter the protein function. The regulation and roles of DPP4 activity are not well understood; therefore, the purpose of this review is to discuss the recent literature regarding DPP4 regulation, as well as the variety of molecules it may affect, and their potential clinical applications. Recent findings Recent insight into the number of proteins that have DPP4 sites, and how DPP4 truncation may alter hematopoiesis based on the protein full length vs. truncated state, has shown that DPP4 truncation of colony-stimulating factors (CSFs) alters their function and that the activity of these CSFs can be enhanced when DPP4 activity is inhibited. DPP4 inhibition has recently been used in a clinical trial to attempt to enhance the engraftment of cord blood cells, and an endogenous DPP4 inhibitor tissue factor pathway inhibitor has been discovered, increasing our understanding of the potential importance of DPP4. Summary DPP4 plays a role in regulating the activity of CSFs and other cytokines involved in hematopoiesis. This information may be useful for enhancing hematopoietic cell transplantation, blood cell recovery after stress, and for understanding the physiology and pathophysiology of blood and other cell systems.

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“…Through enzymatic reactions, DPP4 regulates the activity of biopeptides by proteolytically cleaving many peptides, cytokines, and chemokines [124]. C-X-C Motif Chemokine Ligand 12 (CXCL12) also known as stromal cell-derived factor 1 (SDF1), is a known substrate of DPP4 [125]. CXCL12 binds to the receptors C-X-C Motif Chemokine Receptor 4 (CXCR4) and C-X-C Motif Chemokine Receptor 4 (CXCR7) and thus regulates tumor growth and tumor metastasis [126].…”

Section: Incretin Drugs and Dpp4 Inhibitors In Cancermentioning

confidence: 99%

Cancer Biology and Prevention in Diabetes

Srivastava

Goodwin

2020

Cells

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The available evidence suggests a complex relationship between diabetes and cancer. Epidemiological data suggest a positive correlation, however, in certain types of cancer, a more complex picture emerges, such as in some site-specific cancers being specific to type I diabetes but not to type II diabetes. Reports share common and differential mechanisms which affect the relationship between diabetes and cancer. We discuss the use of antidiabetic drugs in a wide range of cancer therapy and cancer therapeutics in the development of hyperglycemia, especially antineoplastic drugs which often induce hyperglycemia by targeting insulin/IGF-1 signaling. Similarly, dipeptidyl peptidase 4 (DPP-4), a well-known target in type II diabetes mellitus, has differential effects on cancer types. Past studies suggest a protective role of DPP-4 inhibitors, but recent studies show that DPP-4 inhibition induces cancer metastasis. Moreover, molecular pathological mechanisms of cancer in diabetes are currently largely unclear. The cancer-causing mechanisms in diabetes have been shown to be complex, including excessive ROS-formation, destruction of essential biomolecules, chronic inflammation, and impaired healing phenomena, collectively leading to carcinogenesis in diabetic conditions. Diabetes-associated epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndMT) contribute to cancer-associated fibroblast (CAF) formation in tumors, allowing the epithelium and endothelium to enable tumor cell extravasation. In this review, we discuss the risk of cancer associated with anti-diabetic therapies, including DPP-4 inhibitors and SGLT2 inhibitors, and the role of catechol-o-methyltransferase (COMT), AMPK, and cell-specific glucocorticoid receptors in cancer biology. We explore possible mechanistic links between diabetes and cancer biology and discuss new therapeutic approaches.

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CD26 protease inhibition improves functional response of unfractionated cord blood, bone marrow, and mobilized peripheral blood cells to CXCL12/SDF-1

Cited by 11 publications

References 28 publications

Inhibition of Dipeptidyl Peptidase-4 Accelerates Epithelial–Mesenchymal Transition and Breast Cancer Metastasis via the CXCL12/CXCR4/mTOR Axis

Inhibition of Dipeptidyl Peptidase-4 Accelerates Epithelial–Mesenchymal Transition and Breast Cancer Metastasis via the CXCL12/CXCR4/mTOR Axis

The role of dipeptidyl peptidase 4 in hematopoiesis and transplantation

Cancer Biology and Prevention in Diabetes

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