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Rupatadine inhibits colorectal cancer cell proliferation through the PIP5K1A/Akt/CDK2 pathway

Lei Jiang1, Zhibo Zhang1, Zhaofeng Luo2

  • 1China Pharmaceutical University, Nanjing 210000, China; Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Zhuhai 519000, China.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|June 5, 2024
PubMed
Abstract

Insights

Phosphatidylinositol-4-phosphate 5-kinase type 1 alpha (PIP5K1A) promotes colorectal cancer (CRC) progression. Rupatadine targets PIP5K1A, inhibiting CRC cell proliferation via the Akt/GSK-3β pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Phosphatidylinositol-4-phosphate 5-kinase type 1 alpha (PIP5K1A) is implicated in various malignancies.
  • PIP5K1A's role in colorectal cancer (CRC) progression and therapeutic targeting remains underexplored.

Purpose of the Study:

  • To investigate the association between PIP5K1A and CRC progression.
  • To assess the efficacy and mechanism of rupatadine in targeting PIP5K1A for CRC treatment.

Main Methods:

  • PIP5K1A expression and function in CRC were analyzed using tissue chips and proliferation assays.
  • Rupatadine was screened via computational methods and cytotoxicity assays, with its interaction with PIP5K1A confirmed through kinase activity and bio-layer interferometry.
  • In vitro and in vivo pharmacodynamic assays evaluated rupatadine's anti-tumor effects, while molecular mechanisms were explored using qPCR, Western blot, and immunofluorescence.

Main Results:

  • PIP5K1A acts as a proto-oncogene in CRC, with aberrant expression correlating with malignancy.
  • Rupatadine inhibits the PIP5K1A/Akt/GSK-3β pathway, leading to down-regulation of cyclin-dependent kinase 2 and cyclin D1.
  • Rupatadine induces cell cycle arrest and suppresses CRC cell proliferation both in vitro and in vivo.

Conclusions:

  • PIP5K1A represents a promising therapeutic target for CRC.
  • Rupatadine, by targeting PIP5K1A and modulating the Akt/GSK-3β pathway, offers a potential new treatment strategy for CRC.
Keywords:
Cell cycleCell proliferationColorectal cancerPIP5K1ARupatadine

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