A MARCKS Effector Domain-Derived Cytotoxic Peptide Induces Acute Tumor Cell Death

Peptide drugs, with their unique properties of specific therapeutic effects and minimal side effects, are a promising avenue in Cancer treatment. The MARCKS effector domain (ED) peptide has been found to inhibit MARCKS function or induce cell death. In this study, we investigated the cytotoxic efficacy of the non-phosphorylating MARCKS ED peptide with four serine (4S) of ED mutation to alanine (4 A) and with a transactivator of transcription (TAT) (termed 4A-TAT) fusion to improve cell permeating. We found that the 4A-TAT peptide caused acute and robust cytotoxicity against various tumor cell lines and had low toxicity to normal human B cells. Mechanistically, 4A-TAT rapidly disrupts plasma membrane integrity via pore formation, leading to calcium dyshomeostasis and organelle dysfunction, and ultimately inducing non-apoptotic cell death. In addition, the ED4A amino acid component is more critical than its order, and TAT is essential for the high sensitivity of cytotoxicity. Our study suggests that 4A-TAT peptide shows acute and robust killing effects on tumor cells in vitro and in vivo, making it a potentially intriguing cytotoxic peptide for tumor treatment.

4A‐TAT peptide; Cell death; Lymphoma; MARCKS effector domain; membrane disruption.