Delivery of Pleckstrin-Homology Domains Suppresses PI3K/Akt Signaling and Breast Cancer Metastasis

Area of Science:

• Oncology
• Molecular Biology
• Gene Therapy

Background:

• Current cancer therapies are ineffective against metastatic dissemination.
• Obscurin, a large metastasis suppressor protein, is often lost in breast cancer, leading to PI3K/Akt pathway activation.
• Restoring full-length obscurin is challenging due to its large size.

Purpose of the Study:

• To develop a novel therapeutic strategy to inhibit breast cancer metastasis by targeting the PI3K/Akt pathway.
• To engineer a smaller, functional fragment of obscurin for effective delivery and PI3K/Akt inhibition.
• To identify novel metastasis suppressors based on the obscurin mechanism.

Main Methods:

• Adenovirus and lipid nanoparticles were used to deliver a mini-obscurin fragment (obscurin-PH domain) into breast cancer cells.
• The interaction between obscurin-PH domain and PI3K-p85 regulatory subunit was investigated.
• The effects of mini-obscurin on cell migration, adhesion, invasion, and metastasis were assessed.
• Structurally homologous PH domains were tested to identify a broader class of inhibitors.

Main Results:

• Mini-obscurin effectively suppressed PI3K/Akt activity by sequestering the PI3K-p85 subunit.
• This led to the elimination of filopodia and invadopodia, reducing cell migration, adhesion, and invasion.
• Matrix metalloproteinase expression was reduced, blocking cancer dissemination and metastasis.
• A family of nine PH domains with a conserved "p85 inhibitory metastasis suppressor" (PIMS) motif was identified as potential PI3K inhibitors.

Conclusions:

• A novel, non-chemical therapeutic strategy using mini-obscurin PH domains effectively inhibits breast cancer metastasis.
• This approach targets the PI3K-p85 subunit, offering a new avenue for gene therapy in metastatic breast cancer.
• The identification of PIMS-motif containing PH domains provides a foundation for developing new classes of metastasis suppressors.