HMGB1: A Central Node in Cancer Therapy Resistance

Area of Science:

• Molecular Biology
• Cancer Research
• Immunology

Background:

• Cancer therapy resistance is a complex challenge driven by integrated molecular systems allowing tumor cells to survive cytotoxic stress.
• High Mobility Group Box 1 (HMGB1) is recognized as a key regulator of these resistance mechanisms.

Purpose of the Study:

• To review the compartmentalized functions of HMGB1 in mediating cancer therapy resistance.
• To explore the potential of HMGB1-targeted therapies for overcoming treatment evasion.

Main Methods:

• Literature review focusing on the role of HMGB1 in different cellular compartments (nucleus, cytoplasm, extracellular space).
• Analysis of HMGB1's involvement in DNA repair, autophagy, cell death pathways, and immune signaling.
• Examination of emerging therapeutic strategies targeting HMGB1.

Main Results:

• Nuclear HMGB1 enhances DNA repair and chromatin accessibility, conferring resistance to radio- and chemotherapy.
• Cytosolic HMGB1 promotes autophagy, redox stability, and modulates cell death pathways, favoring survival.
• Extracellular HMGB1 acts as a DAMP, activating pro-survival signaling and inflammation, upregulating drug efflux transporters, and reinforcing resistance.

Conclusions:

• HMGB1 functions as a central node in cancer therapy resistance networks through its compartmentalized activities.
• Targeting HMGB1 with novel agents offers potential for reversing resistance, but requires context-specific strategies for clinical translation in refractory cancers.