Statin-Sensitive Akt1/Src/Caveolin-1 Signaling Enhances Oxidative Stress Resistance in Rhabdomyosarcoma.

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Rhabdomyosarcoma (RMS) is a common pediatric soft tissue sarcoma.
• Identifying mechanisms of radioresistance is crucial for improving RMS treatment outcomes.
• The Akt1/Src/Cav1 pathway is implicated in cellular responses to irradiation.

Purpose of the Study:

• To investigate the molecular mechanisms of radioresistance in RMS.
• To evaluate the radiosensitizing potential of inhibiting the Akt1/Src/Cav1 pathway.
• To explore the therapeutic efficacy of statins in combination with radiotherapy for RMS.

Main Methods:

• Irradiation (IR) of human RMS cell lines (RD and RH30).
• Assessment of Akt1, Src, and Cav1 phosphorylation and expression.
• Measurement of reactive oxygen species (ROS) levels and catalase expression.
• Treatment with statins (lovastatin, simvastatin) alone and in combination with IR or actinomycin D.
• Analysis of apoptosis and DNA damage (γH2AX staining, FACS analysis).

Main Results:

• IR transiently increased Akt1, Src, and Cav1 phosphorylation.
• Inhibition of Akt1/Src phosphorylation increased ROS and radiosensitization.
• Overexpression of myristoylated Akt1 (myrAkt1) or Cav1 correlated with radioresistance, reduced ROS, and higher catalase expression.
• Statins reduced Akt1 and Cav1 levels, increased ROS, and promoted apoptosis in RMS cells.
• Combination of statins with IR or actinomycin D enhanced DNA damage, apoptosis, and reduced cell survival.

Conclusions:

• The Akt1/Src/Cav1/catalase molecular signature may predict RMS recurrence risk after radiotherapy.
• Statin-induced oxidative stress represents a potential therapeutic strategy to enhance radiotherapy efficacy in RMS.
• Statins show promise as an adjuvant therapy for improving outcomes in pediatric RMS patients.