Cell-penetrating TIPE2 peptide effectively suppresses tumor migration and progression via targeting RAC1

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Metastasis is a primary cause of cancer mortality, posing a significant clinical challenge.
• Limited cell membrane permeability of therapeutic proteins impedes the clinical application of anti-cancer agents.
• TIPE2, a negative immune regulator, influences inflammation, metabolism, and tumor immunity, indicating its therapeutic potential.

Purpose of the Study:

• To develop a cell-penetrating fusion peptide for enhanced delivery of TIPE2's anti-cancer functions.
• To evaluate the efficacy of the 9R-TIPE2 peptide in inhibiting tumor cell death and migration.
• To assess the in vivo anti-metastatic effects and biosafety of 9R-TIPE2.

Main Methods:

• Construction of a fusion peptide (9R-TIPE2) combining a cell-penetrating sequence (9R) with the TIPE2 α0 domain.
• In vitro assessment of cell membrane permeability, cytotoxicity, and anti-tumor activity in HepG2 and A549 cells.
• In vivo evaluation of anti-metastatic efficacy using a xenograft mouse model with A549 tumors.

Main Results:

• 9R-TIPE2 demonstrated efficient cell membrane penetration and intracellular activity without significant cytotoxicity.
• The peptide induced nutrient deprivation-related tumor cell death and suppressed cancer cell migration by inhibiting RAC1-mediated F-actin polymerization and the mTOR pathway.
• In vivo studies confirmed that 9R-TIPE2 effectively inhibited tumor metastasis in nude mice.

Conclusions:

• 9R-TIPE2 exhibits excellent membrane permeability and biosafety.
• The peptide retains TIPE2's biological functions, inducing tumor cell death and suppressing migration both in vitro and in vivo.
• 9R-TIPE2 represents a promising therapeutic candidate for TIPE2-targeted treatment of various cancers, including hepatocellular carcinoma and lung cancer.