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Targeting the WASF3 Regulatory Complex in Pancreatic Cancer Using Stapled Peptides
Taylor C Dill1, Elliot J Alger2, Sophia Gambale2
1Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Abstract:
Wiskott-Aldrich Syndrome Protein Family (WASF) members form a heteropentameric complex along with ABI1/2, NCKAP1, CYFIP1/2, and BRK1, termed the WASF Regulatory Complex (WRC), which regulates actin cytoskeletal remodeling. Upregulated WASF3 has been identified in pancreatic cancer and is associated with a poor prognosis, increased invasion, and metastasis. In this study, we sought to determine whether disruption of the WRC could suppress WASF3-mediated actin polymerization and subsequent cellular invasion and motility in pancreatic cancer cells. Here, we screened constrained peptides designed to disrupt the formation of the WRC at multiple protein-protein interfaces. The WASF3-derived constrained peptide WAHM1 was found to suppress cell motility and invasion in PANC-1 and BxPC-3 cells. Further, WAHM1 was found to permeate pancreatic cancer cell lines, bind to its protein targets in the WRC, and reduce WRC protein levels. WAHM1 may serve as a complementary strategy to downregulate WASF3-mediated migration and invasion in pancreatic cancer models.
Insights
A novel peptide, WAHM1, disrupts the WASF Regulatory Complex (WRC) in pancreatic cancer cells. This disruption suppresses tumor cell invasion and migration, offering a potential new therapeutic strategy.
Area of Science:
- Cell Biology
- Molecular Oncology
- Biochemistry
Background:
- Wiskott-Aldrich Syndrome Protein Family (WASF) members, including WASF3, are crucial for actin cytoskeletal remodeling.
- Elevated WASF3 expression in pancreatic cancer correlates with poor prognosis, increased invasion, and metastasis.
- The WASF Regulatory Complex (WRC) is a key regulator of WASF protein function.
Purpose of the Study:
- To investigate if disrupting the WRC can inhibit WASF3-driven actin polymerization, cellular invasion, and motility in pancreatic cancer.
- To identify specific molecular strategies targeting the WRC for therapeutic intervention in pancreatic cancer.
Main Methods:
- Screening of constrained peptides designed to interfere with WRC protein-protein interactions.
- Evaluation of peptide efficacy in suppressing pancreatic cancer cell lines (PANC-1, BxPC-3).
- Assessment of peptide cellular permeability, target binding, and WRC protein level reduction.
Main Results:
- A WASF3-derived peptide, WAHM1, effectively suppressed pancreatic cancer cell motility and invasion.
- WAHM1 demonstrated cellular permeability and specific binding to WRC targets within pancreatic cancer cells.
- Treatment with WAHM1 led to a reduction in WRC protein levels.
Conclusions:
- Disruption of the WRC using the peptide WAHM1 is a viable strategy to inhibit pancreatic cancer cell invasion and migration.
- WAHM1 shows promise as a potential therapeutic agent to downregulate WASF3-mediated processes in pancreatic cancer.
- Targeting the WRC represents a novel approach for developing complementary therapies for pancreatic cancer.