TP5: A Novel Therapeutic Approach Targeting Aberrant and Hyperactive CDK5/p25 for the Treatment of Colorectal Carcinoma - Aix-Marseille Université Accéder directement au contenu
Article Dans Une Revue International Journal of Molecular Sciences Année : 2023

TP5: A Novel Therapeutic Approach Targeting Aberrant and Hyperactive CDK5/p25 for the Treatment of Colorectal Carcinoma

Niranjana Amin
  • Fonction : Auteur
Herui Wang
Qi Song
  • Fonction : Auteur
Manju Bhaskar
  • Fonction : Auteur
Sharda Prasad Yadav
  • Fonction : Auteur
Mark Gilbert
  • Fonction : Auteur
Harish Pant
  • Fonction : Auteur
Emeline Tabouret
Zhengping Zhuang
  • Fonction : Auteur

Résumé

Colorectal carcinoma (CRC) is a prevalent cancer worldwide with a high mortality rate. Evidence suggests that increased expression of Cyclin-dependent kinase 5 (CDK5) contributes to cancer progression, making it a promising target for treatment. This study examined the efficacy of selectively inhibiting CDK5 in colorectal carcinoma using TP5, a small peptide that selectively inhibits the aberrant and hyperactive CDK5/p25 complex while preserving physiological CDK5/p35 functions. We analyzed TP5’s impact on CDK5 activity, cell survival, apoptosis, the cell cycle, DNA damage, ATM phosphorylation, and reactive oxygen species (ROS) signaling in mitochondria, in CRC cell lines, both alone and in combination with chemotherapy. We also assessed TP5’s efficacy on a xenograft mouse model with HCT116 cells. Our results showed that TP5 decreased CDK5 activity, impaired cell viability and colony formation, induced apoptosis, increased DNA damage, and led to the G1 phase arrest of cell cycle progression. In combination with irinotecan, TP5 demonstrated a synergy by leading to the accumulation of DNA damage, increasing the γH2A.X foci number, and inhibiting G2/M arrest induced by Sn38 treatment. TP5 alone or in combination with irinotecan increased mitochondrial ROS levels and inhibited tumor growth, prolonging mouse survival in the CRC xenograft animal model. These results suggest that TP5, either alone or in combination with irinotecan, is a promising therapeutic option for colorectal carcinoma.

Dates et versions

hal-04452579 , version 1 (12-02-2024)

Identifiants

Citer

Niranjana Amin, Herui Wang, Qi Song, Manju Bhaskar, Sharda Prasad Yadav, et al.. TP5: A Novel Therapeutic Approach Targeting Aberrant and Hyperactive CDK5/p25 for the Treatment of Colorectal Carcinoma. International Journal of Molecular Sciences, 2023, 24 (14), pp.11733. ⟨10.3390/ijms241411733⟩. ⟨hal-04452579⟩
5 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More