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Tumor cells express and maintain HMGB1 in the reduced isoform to enhance CXCR4-mediated migration

ABSTRACT: During inflammation and tissue regeneration, the alarmin High Mobility Group Box 1 (HMGB1), in its reduced isoform, enhances the activity of the chemokine CXCL12, forming a heterocomplex that acts via the chemokine receptor CXCR4. Despite the established roles of both HMGB1 and CXCL12 in tumor progression and metastatic spread to distal sites, the role of the CXCL12/HMGB1 heterocomplex in cancer has never been investigated. By employing a newly established mass spectrometry protocol that allows an unambiguous distinction between reduced (red HMGB1) and oxidized (ox HMGB1) HMGB1 isoforms in cell lysates, we demonstrate that human epithelial cells derived from breast (MCF-7 and MDA-MB-231) and prostate (PC-3) cancer predominantly express red-HMGB1, while primary CD3+ T lymphocytes from peripheral blood express both HMGB1 isoforms. All these cancer cells release HMGB1 in the extracellular microenvironment together with varying concentrations of thioredoxin and thioredoxin reductase. The CXCL12/HMGB1 heterocomplex enhances, via CXCR4, the directional migration and invasiveness of cancer cells characterized by high metastatic potential that possess a fully active thioredoxin system, contributing to maintain red-HMGB1. On the contrary, cancer cells with low metastatic potential, lack thioredoxin reductase, promptly uptake CXCL12 and fail to respond to the heterocomplex. Our study demonstrates that the responsiveness of cancer cells to the CXCL12/HMGB1 heterocomplex, resulting in enhanced cell migration and invasiveness, depends on the maintenance of HMGB1 in its reduced isoform, and suggests disruption of the heterocomplex as a potential therapeutic target to inhibit invasion and metastatic spread in cancer therapies.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Matteo Pecoraro

LAB HEAD: Mariagrazia Uguccioni

PROVIDER: PXD048091 | Pride | 2024-05-02

REPOSITORIES: Pride

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			Action	DRS
	20200402_MaPe_EdPi_SA_BG_Hmgb1_Lau_1ug_ABC.raw	Raw
	20210608_MP018_EdPi_SA_MCF7_DDA.raw	Raw
	20210928_MP033_EdPi_SA_MCF7_LysC.raw	Raw
	20220209_MP046_EdPi_SA_PC3.raw	Raw
	20220407_MP052_EdPi_SA_MCF7.raw	Raw

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Tumor cells express and maintain HMGB1 in the reduced isoform to enhance CXCR4-mediated migration

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