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GK-1 Induces Oxidative Stress, Mitochondrial Dysfunction, Decreased Membrane Potential, and Impaired Autophagy Flux
Alfredo Cruz-Gregorio1, Ana Karina Aranda-Rivera1, Omar Emiliano Aparicio-Trejo2
1Laboratorio F-315, Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico City 04510, Mexico.
Abstract:
Breast cancer (BC) is the second most common cancer worldwide in women. During the last decades, the mortality due to breast cancer has progressively decreased due to early diagnosis and the emergence of more effective new treatments. However, human epidermal growth factor receptor 2 (HER2) and triple-negative breast cancer (TNBC) remain with poor prognoses. In our research group, we are proposing the GK-1 immunomodulatory peptide as a new alternative for immunotherapy of these aggressive tumors. GK-1 reduced the growth rate of established tumors and effectively reduced lung metastasis in the 4T1 experimental murine model of breast cancer. Herein, the effect of GK-1 on the redox state, mitochondrial metabolism, and autophagy of triple-negative tumors that can be linked to cancer evolution was studied. GK-1 decreased catalase activity, reduced glutathione (GSH) content and GSH/oxidized glutathione (GSSG) ratio while increased hydrogen peroxide (H2O2) production, GSSG, and protein carbonyl content, inducing oxidative stress (OS) in tumoral tissues. This imbalance between reactive oxygen species (ROS) and antioxidants was related to mitochondrial dysfunction and uncoupling, characterized by reduced mitochondrial respiratory parameters and dissipation of mitochondrial membrane potential (ΔΨm), respectively. Furthermore, GK-1 likely affected autophagy flux, confirmed by elevated levels of p62, a marker of autophagy flux. Overall, the induction of OS, dysfunction, and uncoupling of the mitochondria and the reduction of autophagy could be molecular mechanisms that underlie the reduction of the 4T1 breast cancer induced by GK-1.
Insights
The novel GK-1 peptide combats aggressive breast cancers, including triple-negative breast cancer (TNBC), by inducing oxidative stress and mitochondrial dysfunction. This immunotherapy approach shows promise in reducing tumor growth and metastasis in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Metabolism
Background:
- Breast cancer (BC) is a leading cause of cancer death in women, with HER2-positive and triple-negative breast cancer (TNBC) subtypes exhibiting poor prognoses.
- Current treatments have improved survival rates, but aggressive subtypes necessitate novel therapeutic strategies.
- Immunomodulatory peptides represent a promising avenue for cancer immunotherapy.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the anti-cancer effects of the GK-1 immunomodulatory peptide in a triple-negative breast cancer (TNBC) model.
- To assess the impact of GK-1 on oxidative stress, mitochondrial function, and autophagy in 4T1 breast cancer cells.
- To elucidate how GK-1 influences tumor growth and metastasis.
Main Methods:
- Utilized the 4T1 murine model of breast cancer to evaluate GK-1 efficacy.
- Assessed oxidative stress markers including catalase activity, glutathione (GSH) levels, GSH/GSSG ratio, hydrogen peroxide (H2O2) production, and protein carbonyl content.
- Analyzed mitochondrial function through respiratory parameters and mitochondrial membrane potential (ΔΨm) measurements.
- Investigated autophagy flux by quantifying p62 levels.
Main Results:
- GK-1 treatment significantly reduced tumor growth rate and lung metastasis in the 4T1 model.
- GK-1 induced significant oxidative stress in tumoral tissues, evidenced by decreased GSH and increased H2O2 and GSSG.
- Mitochondrial dysfunction, characterized by reduced respiration and membrane potential dissipation, was observed.
- Evidence suggests GK-1 disrupts autophagy flux, indicated by elevated p62 levels.
Conclusions:
- GK-1 demonstrates potent anti-cancer activity against aggressive breast cancer models.
- The therapeutic effects of GK-1 are mediated by the induction of oxidative stress and mitochondrial dysfunction.
- GK-1's impact on autophagy flux may also contribute to its anti-tumorigenic properties, highlighting its potential as a novel immunotherapy.
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