Antibiotic-disrupted ribosome biogenesis facilitates tumor chemokine superinduction

Ki-Hyung Kim; Arulkumar Nagappan; BoGyoung Song; Sehun Lim; Yuseok Moon

doi:10.1016/j.bcp.2022.115303

Antibiotic-disrupted ribosome biogenesis facilitates tumor chemokine superinduction

Biochem Pharmacol. 2022 Dec:206:115303. doi: 10.1016/j.bcp.2022.115303. Epub 2022 Oct 23.

Authors

Ki-Hyung Kim¹, Arulkumar Nagappan², BoGyoung Song², Sehun Lim³, Yuseok Moon⁴

Affiliations

¹ Laboratory of Mucosal Exposome and Biomodulation, Department of Integrative Biomedical Sciences, Pusan National University, Yangsan, South Korea; Department of Obstetrics and Gynecology, College of Medicine, Pusan National University, Pusan National University, Busan, South Korea; Biomedical Research Institute, Pusan National University, Busan, South Korea.
² Laboratory of Mucosal Exposome and Biomodulation, Department of Integrative Biomedical Sciences, Pusan National University, Yangsan, South Korea.
³ Department of Anesthesiology and Pain Medicine, Inje University Busan Paik Hospital, Busan, South Korea.
⁴ Laboratory of Mucosal Exposome and Biomodulation, Department of Integrative Biomedical Sciences, Pusan National University, Yangsan, South Korea; Biomedical Research Institute, Pusan National University, Busan, South Korea; Graduate Program of Genomic Data Sciences, Pusan National University, Yangsan 50612, South Korea. Electronic address: moon@pnu.edu.

PMID: 36283446
DOI: 10.1016/j.bcp.2022.115303

Abstract

Upon exposure to internal or external stressors, ribosomes stand sentinel via modulation of ribosome assembly and protein translation. Ribosome-dependent cellular dysfunctions have been associated with pathophysiological processes during inflammation and tumorigenesis. In the present study, ribosome biogenesis was assessed to determine its effects on tumor chemokines, potentially contributing to cancer cell malignant features. In particular, ribosome biogenesis inhibition by antibiotic actinomycin D (ActD) enhanced the expression of chemokines in intestinal cancer cells under endoplasmic reticulum stress that governs multiple pro-tumoral reprogramming. Mechanistically, ribosome biogenesis inhibition superinduced proinflammatory chemokines via transcriptional and post-transcriptional regulation. Moreover, ribosomal stress-responsive p53 and its target macrophage inhibitory cytokine 1 (MIC-1) mediated chemokine superinduction by activating TGF-β-activated kinase 1 (TAK-1) and nuclear factor-kappa B (NF-κB) in intestinal cancer cells. Cancer cell-based regulation of chemokine induction via MIC-1 signaling was verified using clinical transcriptome datasets. Clinical tumor tissue-derived MIC-1 was a positive regulator of chemokines and genes involved in the ribosome biogenesis pathway, supporting the in vitro assessments. Moreover, MIC-1-correlated chemokine expressions predicted poor prognoses in patients with colorectal cancer. Ribosome-based chemokine regulation via MIC-1 signaling would provide novel insights into translational interventions against malignant inflammatory insults.

Keywords: Cancer chemokines; Endoplasmic reticulum stress; MIC-1; P53; Ribosome biogenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents* / metabolism
Anti-Bacterial Agents* / pharmacology
Chemokines / genetics
Chemokines / metabolism
Humans
NF-kappa B / metabolism
Neoplasms* / metabolism
Ribosomes / metabolism

Substances

Anti-Bacterial Agents
Chemokines
NF-kappa B