A feedback mechanism from prostate cancer cells to macrophages, reinforced by STAT1, regulates tumor progression and resistance to radiotherapy

TL;DR

This study reveals a feedback loop involving prostate cancer cells and macrophages that drives cancer progression and resistance to radiotherapy.

Contribution

The study identifies a novel STAT1/lactate/NFκB1/MCP-1 feedback mechanism linking prostate cancer cells and macrophages.

Findings

STAT1 increases lactate production in prostate cancer cells.

Lactate activates macrophages to promote M2 polarization and MCP-1 secretion.

MCP-1 activates JAK/STAT1 in cancer cells, enhancing tumor progression and radioresistance.

Abstract

The resistance to radiotherapy of prostate cancer is driven by interactions within the tumor microenvironment, particularly between prostate cancer cells and tumor-associated macrophages, however the underlying mechanisms remain poorly understood. In this study, we found that STAT1 enhanced the transcription of critical glycolytic enzymes, leading to an increase in lactate secretion from prostate cancer cells. Then, the lactate was transported to macrophages via the MCT1 transporter, activating the NFκB1 pathway, which subsequently promoted macrophage polarization to the M2 phenotype and activated the transcription of MCP-1. MCP-1 was secreted from macrophages interacted with the CCR2 receptor on prostate cancer cells, thereby activating the JAK/STAT1 pathway, ultimately contributing to the progression of prostate cancer and its resistance to radiotherapy. Taken together, our findings identified a STAT1/lactate/NFκB1/MCP-1 positive feedback mechanism as a driver of prostate cancer progression and resistance to radiotherapy that functioned by interaction to macrophages, which could be potential therapeutic targets for the advanced prostate cancer.

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