Rebound increases in chemokines by CXCR2 antagonist in breast cancer can be prevented by PKCδ and PKCε activators
| Autor: | Patrícia Rijo, Esra Tavşan, Özlem Akdeniz, Nuray Erin, Vera M. S. Isca |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cyclopropanes Chemokine Indoles Bryostatin 1 Immunology Chemokine CXCL2 Enzyme Activators Mammary Neoplasms Animal Protein Kinase C-epsilon Biochemistry p38 Mitogen-Activated Protein Kinases Receptors Interleukin-8B 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Alkanes Immunology and Allergy Animals Secretion CXC chemokine receptors Extracellular Signal-Regulated MAP Kinases Molecular Biology Protein kinase C Cell Proliferation Mice Inbred BALB C biology Chemistry Phenylurea Compounds Hematology respiratory system Bryostatins CXCL1 CXCL2 Protein Kinase C-delta 030104 developmental biology 030220 oncology & carcinogenesis Chemokine secretion biology.protein Cancer research Female Chemokines Diterpenes |
| Zdroj: | Cytokine. 142 |
| ISSN: | 1096-0023 |
| Popis: | Activation of CXCR2 by chemokines such as CXCL1 and CXCL2 increases aggressiveness of breast cancer, inducing chemoresistance, hence CXCR2 antagonists are in clinical trials. We previously reported that inhibition of CXCR2 increases MIP-2 (CXCL2), which may inhibit anti-tumoral effects of CXCR2 antagonists. This seems to be due to inhibition of protein kinase C (PKC) by CXCR2 antagonist since specific inhibitor of PKC also enhances MIP-2 secretion. We here examined whether CXCR2 inhibitor also increases KC (CXCL1) secretion, ligand for CXCR2 involved in metastasis and PKC activators can prevent increases in chemokine secretion. We used SB 225002, which is a specific CXCR2 antagonist. The effects of PKC activators that have documented anti-tumoral effects and activates multiple isozymes of PKC such as Ingenol-3-angelate (I3A) and bryostatin-1 were examined here. In addition, FR236924, PKCe selective and 7α-acetoxy-6β-benzoyloxy-12-O-benzoylroyleanone (Roy-Bz), PKCδ selective activators were also tested. The effects of activators were determined using brain metastatic (4TBM) and heart metastatic (4THM) subset of 4T1 breast carcinoma cells because these aggressive carcinoma cells with cancer stem cell features secrete high levels of KC and MIP-2. Inhibition of CXCR-2 activity increased KC (CXCL1) secretion. PKC activators prevented SB225002-induced increases in KC and MIP-2 secretion. Different activators/modulators induce differential changes in basal and SB225002-induced chemokine secretion as well as cell proliferation and the activators that act on PKCδ and/or PKCe such as bryostatin 1, FR236924 and Roy-Bz are the most effective. These activators alone also decrease cell proliferation or chemokine secretion or both. Given the role of KC and MIP-2 in drug resistance including chemotherapeutics, activators of PKCe and PKCδ may prevent emerging of resistance to CXCR2 inhibitors as well as other chemotherapeutics. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect