Therapeutic targeting of SPIB/SPI1-facilitated interplay of cancer cells and neutrophils inhibits aerobic glycolysis and cancer progression.

Abstract

BACKGROUND:

As a metabolic reprogramming feature, cancer cells derive most of their energy from aerobic glycolysis, while its regulatory mechanisms and therapeutic strategies continue to be illusive.

METHODS:

Integrative analysis of publically available expression profile datasets was used to identify critical transcriptional regulators and their target glycolytic enzymes. The functions and acting mechanisms of transcriptional regulators in cancer cells were investigated by using in vitro and in vivo assays. The Kaplan-Meier curve and log-rank assay were used to conduct the survival study.

RESULTS:

Salmonella pathogenicity island 1 (SPI1/PU.1), a haematopoietic transcription factor, was identified to facilitate glycolytic process, tumourigenesis, invasiveness, as well as metastasis of colon cancer cells, which was interplayed by tumour-associated neutrophils. Mechanistically, neutrophils delivered SPI1 mRNA via extracellular vesicles, resulting in enhanced SPI1 expression of cancer cells. Through physical interaction with SPI1-related protein (SPIB), SPI1 drove expression of glycolytic genes within cancer cells, which in turn induced polarization of neutrophils via glycolytic metabolite lactate. Depletion of neutrophils or SPIB-SPI1 interaction in cancer cells significantly inhibited glycolytic process, tumourigenesis and aggressiveness. Upregulation of SPI1 or SPIB was found to be associated with poor prognosis in patients suffering from colon cancer.

CONCLUSIONS:

Therapeutic targeting of SPIB/SPI1-facilitated interplay of cancerous cells and neutrophils suppresses aerobic glycolysis and progression of cancer.

• Authors: Jianqun Wang, Xiaojing Wang, Yanhua Guo, Lin Ye, Dan Li, Anpei Hu, Shuang Cai, Boling Yuan, Shikai Jin, Yi Zhou, Qilan Li, Liduan Zheng, Qiangsong Tong
• Journal: Clinical and translational medicine (Clin Transl Med) Vol. 11 Issue 11 Pg. e588 (11 2021) ISSN: 2001-1326 [Electronic] United States
• PMID: 34841706 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

Chemical References

• Proto-Oncogene Proteins
• Trans-Activators
• proto-oncogene protein Spi-1

Topics

• Cell Line (metabolism)
• Disease Progression
• Humans
• Neutrophils (drug effects, physiology)
• Proto-Oncogene Proteins (pharmacology, therapeutic use)
• Trans-Activators (pharmacology, therapeutic use)
• Warburg Effect, Oncologic (drug effects)