M1-NP1 Interfering-Peptide Inhibits Cancer Cell Proliferation and Migration by Targeting FOXM1

Forkhead box M1 (FOXM1) is a transcription factor frequently overexpressed in numerous cancers, playing a critical role in cell cycle progression, proliferation, and tumor metastasis. Its widespread involvement in oncogenesis makes FOXM1 an attractive target for novel anti-cancer therapies. Current cancer treatments often face challenges with specificity and systemic side effects, highlighting the urgent need for targeted approaches that can selectively inhibit key oncogenic drivers. Developing agents that can directly interfere with FOXM1's function or its protein interactions represents a promising strategy to overcome these limitations and develop more effective and safer cancer drugs.

Researchers employed yeast-two-hybrid (Y2H) screening to identify M1-NP1 as a novel peptide specifically targeting FOXM1. The study then investigated M1-NP1's effects on cancer cells (unspecified type) in vitro, assessing parameters such as cell cycle progression, migration, and FOXM1 transcriptional activities. Mechanistic studies involved evaluating M1-NP1's binding to FOXM1 and its impact on interactions with polo-like kinase 1 (PLK1) and CREB binding protein (CBP), as well as FOXM1's subcellular distribution. Furthermore, the anti-cancer efficacy and safety of M1-NP1 were evaluated in vivo using wild-type mice, though specific doses, routes of administration, or the presence of a tumor model were not detailed in the abstract. Safety assessments included immunogenicity, hemolysis, stability, and distribution in mice.

M1-NP1 bound to the C-terminal region of FOXM1 and disrupted its interactions with the cell cycle-related kinase PLK1 and the transcriptional co-activator CBP. This disruption directly inhibited FOXM1 transcriptional activities, which are crucial for cell proliferation. Additionally, M1-NP1 significantly affected FOXM1 distribution within cells, actively preventing the transcription factor from infiltrating the nucleus where it exerts its pro-cancer effects. Gene expression analysis further revealed that M1-NP1 treatment in cancer cells downregulated gene sets associated with cell cycle phase transition, while simultaneously upregulating gene sets related to cell adhesion, indicating a shift towards a less proliferative and migratory phenotype. > The novel peptide M1-NP1 directly targets the C-terminal region of FOXM1, disrupting its critical interactions with PLK1 and CBP, thereby inhibiting its transcriptional activity and nuclear localization. Moreover, the anti-cancer effects of M1-NP1 were confirmed in wild-type mice, where it demonstrated efficacy without any notable toxic or side effects, suggesting a favorable safety profile. Further safety indications included low levels of immunogenicity and hemolysis, alongside a good profile for stability and distribution in mice, which are critical factors for potential therapeutic development.