2. Academic Validation
  3. Rupatadine inhibits colorectal cancer cell proliferation through the PIP5K1A/Akt/CDK2 pathway

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

  • Biomed Pharmacother. 2024 Jul:176:116826. doi: 10.1016/j.biopha.2024.116826.
Lei Jiang 1,  Zhibo Zhang 1,  Zhaofeng Luo 2,  Luan Li 3,  Shengtao Yuan 4,  Min Cui 5,  Ke He 6,  Jing Xiao 7
Affiliations

Affiliations

  • 1 China 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.
  • 2 Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
  • 3 Department of Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China.
  • 4 China Pharmaceutical University, Nanjing 210000, China.
  • 5 Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Zhuhai 519000, China. Electronic address: CM_zhrmyy@163.com.
  • 6 Minimally Invasive Tumor Therapies Center, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510310, China. Electronic address: hiker00006@126.com.
  • 7 Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Zhuhai 519000, China; Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau SAR, China. Electronic address: nfxj2009@163.com.
PMID: 38838507 DOI: 10.1016/j.biopha.2024.116826
Abstract

Background: Phosphatidylinositol-4-phosphate 5-kinase type 1 alpha (PIP5K1A) acts upstream of the Akt regulatory pathway and is abnormally expressed in many types of malignancies. However, the role and mechanism of PIP5K1A in colorectal Cancer (CRC) have not yet been reported. In this study, we aimed to determine the association between PIP5K1A and progression of CRC and assess the efficacy and mechanism by which rupatadine targets PIP5K1A.

Methods: Firstly, expression and function of PIP5K1A in CRC were investigated by human colon Cancer tissue chip analysis and cell proliferation assay. Next, rupatadine was screened by computational screening and cytotoxicity assay and interactions between PIP5K1A and rupatadine assessed by kinase activity detection assay and bio-layer interferometry analysis. Next, rupatadine's anti-tumor effect was evaluated by in vivo and in vitro pharmacodynamic assays. Finally, rupatadine's anti-tumor mechanism was explored by quantitative real-time reverse-transcription polymerase chain reaction, western blot, and immunofluorescence.

Results: We found that PIP5K1A exerts tumor-promoting effects as a proto-oncogene in CRC and aberrant PIP5K1A expression correlates with CRC malignancy. We also found that rupatadine down-regulates cyclin-dependent kinase 2 and cyclin D1 protein expression by inhibiting the PIP5K1A/Akt/GSK-3β pathway, induces cell cycle arrest, and inhibits CRC cell proliferation in vitro and in vivo.

Conclusions: PIP5K1A is a potential drug target for treating CRC. Rupatadine, which targets PIP5K1A, could serve as a new option for treating CRC, its therapeutic mechanism being related to regulation of the Akt/GSK-3β signaling pathway.

Keywords

Cell cycle; Cell proliferation; Colorectal cancer; PIP5K1A; Rupatadine.

Figures
Products