Suppression of Breast Cancer Metastasis Using Stapled Peptides Targeting the WASF Regulatory Complex
John K Cowell1, Yong Teng1, N George Bendzunas2
1Georgia Cancer Center, Augusta University, Augusta, GA, USA.
Abstract:
The WASF3 gene facilitates the metastatic phenotype, and its inactivation leads to suppression of invasion and metastasis regardless of the genetic background of the cancer cell. This reliance on WASF3 to facilitate metastasis suggests that targeting its function could serve as an effective strategy to suppress metastasis. WASF3 stability and function are regulated by the WASF Regulatory Complex (WRC) of proteins, particularly CYFIP1 and NCKAP1. Knockdown of these proteins in vitro leads to disruption of the WRC and suppression of invasion. We have used mouse xenograft models of breast cancer metastasis to assess whether targeting the WRC complex suppresses metastasis in vivo. Stapled peptides targeting the WASF3-CYFIP1 interface (WAHM1) and the CYFIP1-NCKAP1 interface (WANT3) suppress the development of lung and liver metastases. Targeting these critical protein-protein interactions, therefore, could potentially be developed into a therapeutic strategy to control cancer cell invasion and metastasis.
Insights
Targeting the WASF3 gene and its regulatory complex (WRC) can suppress cancer metastasis. Novel peptides blocking key protein interactions within the WRC effectively reduced lung and liver metastases in mouse models.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The WASF3 gene is crucial for cancer cell invasion and metastasis.
- WASF3 function is regulated by the WASF Regulatory Complex (WRC), involving proteins like CYFIP1 and NCKAP1.
- Disrupting the WRC complex in vitro suppresses cancer cell invasion.
Purpose of the Study:
- To investigate the in vivo efficacy of targeting the WRC complex to suppress cancer metastasis.
- To evaluate the potential of targeting protein-protein interactions within the WRC as a therapeutic strategy.
Main Methods:
- Utilized mouse xenograft models of breast cancer metastasis.
- Developed stapled peptides (WAHM1 and WANT3) to target specific interfaces within the WRC (WASF3-CYFIP1 and CYFIP1-NCKAP1).
- Assessed the impact of these peptides on metastasis to the lung and liver.
Main Results:
- Targeting the WASF3-CYFIP1 interface with WAHM1 suppressed metastasis.
- Targeting the CYFIP1-NCKAP1 interface with WANT3 also suppressed metastasis.
- Both peptides effectively reduced lung and liver metastases in vivo.
Conclusions:
- The WRC complex is a viable therapeutic target for inhibiting cancer metastasis.
- Targeting critical protein-protein interactions within the WRC using peptides shows promise for developing novel anti-metastatic therapies.
- This approach offers a potential strategy to control cancer cell invasion and spread.
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