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Open AccessArticle

MCP-1/MCPIP-1 Signaling Modulates the Effects of IL-1β in Renal Cell Carcinoma through ER Stress-Mediated Apoptosis

1
National Institute of Cancer Research, National Health Research Institutes, Zhunan 35053, Taiwan
2
Department of Nephrology, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
3
Department of Health Risk Management, College of Public Health, China Medical University, Taichung 40402, Taiwan
4
Department of Urology, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
5
Department of Medical Research, School of Medicine, Chung Gung University, Taoyuan 33302, Taiwan
6
Department of Anatomy and Physiology, Institute of Computational Comparative Medicine, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(23), 6101; https://doi.org/10.3390/ijms20236101
Received: 9 October 2019 / Revised: 21 November 2019 / Accepted: 29 November 2019 / Published: 3 December 2019
In renal cell carcinoma (RCC), interleukin (IL)-1β may be a pro-metastatic cytokine. However, we have not yet noted the clinical association between tumoral expression or serum level of IL-1β and RCC in our patient cohort. Herein, we investigate molecular mechanisms elicited by IL-1β in RCC. We found that IL-1β stimulates substantial monocyte chemoattractant protein (MCP)-1 production in RCC cells by activating NF-kB and AP-1. In our xenograft RCC model, intra-tumoral MCP-1 injection down-regulated Ki67 expression and reduced tumor size. Microarray analysis revealed that MCP-1 treatment altered protein-folding processes in RCC cells. MCP-1-treated RCC cells and xenograft tumors expressed MCP-1-induced protein (MCPIP) and molecules involved in endoplasmic reticulum (ER) stress-mediated apoptosis, namely C/EBP Homologous Protein (CHOP), protein kinase-like ER kinase (PERK), and calnexin (CNX). ER stress-mediated apoptosis in MCP-1-treated RCC cells was confirmed using Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay. Moreover, ectopic MCPIP expression increased PERK expression in Human embryonic kidney (HEK)293 cells. Our meta-analysis revealed that low MCP-1 levels reduce 1-year post-nephrectomy survival in patients with RCC. Immunohistochemistry indicated that in some RCC biopsy samples, the correlation between MCP-1 or MCPIP expression and tumor stages was inverse. Thus, MCP-1 and MCPIP potentially reduce the IL-1β-mediated oncogenic effect in RCC; our findings suggest that ER stress is a potential RCC treatment target. View Full-Text
Keywords: interleukin-1β; chemoattractant protein-1; renal cell carcinoma; monocyte chemoattractant protein (MCP)-induced protein-1; endoplasmic reticulum stress; apoptosis interleukin-1β; chemoattractant protein-1; renal cell carcinoma; monocyte chemoattractant protein (MCP)-induced protein-1; endoplasmic reticulum stress; apoptosis
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Lee, C.-H.; Hung, P.-F.; Lu, S.-C.; Chung, H.-L.; Chiang, S.-L.; Wu, C.-T.; Chou, W.-C.; Sun, C.-Y. MCP-1/MCPIP-1 Signaling Modulates the Effects of IL-1β in Renal Cell Carcinoma through ER Stress-Mediated Apoptosis. Int. J. Mol. Sci. 2019, 20, 6101.

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