Toward Mitochondrial Targeting of Resistant Triple-Negative Breast Cancer Using Triphenylphosphonium-Conjugated...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Therapeutic resistance and metastasis are major challenges in cancer treatment.
• Chemoresistant cells and cancer stem cells (CSCs) often rely on mitochondrial oxidative phosphorylation (OXPHOS) for energy, unlike therapy-sensitive cells that use glycolysis.
• Targeting OXPHOS presents a potential strategy to overcome therapeutic resistance.

Purpose of the Study:

• To investigate the potential of short antimicrobial peptides to suppress metastatic potential and CSC formation in chemoresistant cancer cells.
• To evaluate the efficacy of TPP-conjugated peptides in targeting OXPHOS-dependent resistance.

Main Methods:

• Utilized a triple-negative breast cancer model.
• Administered short antimicrobial peptides and TPP-conjugated peptides.
• Assessed metastatic potential and CSC-like mammosphere formation.
• Conducted mechanistic studies on oxidative stress, mitophagy, and mitochondrial translation.

Main Results:

• Short antimicrobial peptides significantly suppressed the metastatic potential of resistant cancer cells.
• These peptides reduced the formation of CSC-like mammospheres by disrupting mitochondrial respiration.
• TPP conjugation enhanced the anti-cancer effects.
• Mechanistic studies showed induction of oxidative stress, mitophagy, and suppression of mitochondrial translation.

Conclusions:

• TPP-conjugated peptides are a promising therapeutic strategy for targeting OXPHOS-dependent resistance in aggressive solid tumors.
• Disrupting mitochondrial respiration offers a novel approach to combatting therapeutic resistance and metastasis.