Investigating the structural basis of piperine targeting AKT1 against prostate cancer through in vitro and molecular dynamics simulations

Abstract

AkT1, significantly impacts many tumours cell functions, like transcription, apoptosis, glucose metabolism, cell proliferation, and cell migration. For tumours to develop and spread, aberrant activation of AKT1 is essential. Therefore, a major focus of molecularly targeted PCa treatment is AKT1. The present study investigates the effect of piperine compared to SDF using in-vitro studies, viz colony formation assay, comet assay and AKT1 gene expression studies using human PCa cell line PC3. A cluster of approximately at least 50 cells constitutes a colony. The clonogenic assay showed that the number and size of colonies significantly decreased when treated with compounds (SDF and piperine) in comparison to the untreated cells which effectively proliferated to form more colonies. Piperine treatment showed significant inhibition of colony formation than SDF. Effective genotoxicity was observed in piperine-treated PC3 cells with an increased Tail length of 120 µm and it was moderately observed in SDF with a Tail length of 30 µm treated on PC3 cells. The control group did not show any considerable genotoxicity with a Tail length of 6 µm. Our data, both in vitro and in silico, suggested that piperine would be a good starting point for developing novel drugs for the treatment of PCa. The downstream functions of Akt1 may be inhibited by these effects, which could impede the proliferation of PCa cells. High stability of the piperine-AKT1 complex was found by the MD simulation. Higher hydrophilic residues like Lys268 and Ser205 at the active pocket may be the cause of the binding stability. Overall, the observed results confirmed the anti-PCa effect of piperine by causing effective DNA damage and proved to be genotoxic in nature against the human PCa. These effects may impede the downstream activities of Akt1 and result in PCa cell growth regression.

Communicated by Ramaswamy H. Sarma

Keywords:

• Prostate cancer
• AKT1
• piperine
• molecular dynamic simulations
• principal component analysis

Acknowledgments

The authors thank Kuvempu University, Shivamogga, Karnataka, India for providing the necessary facility to carry out the work and the Government of India, Ministry of Tribal Affairs, for the financial support (Award No: 201920-NFST-KAR-01266).

Authors’ contributions

Nayana Prakash: Investigation, Writing—original draft, Visualization. Pavan Gollapalli: Investigation, Writing—original draft, Methodology. Manjunatha Hanumanthappa: Investigation, review & editing.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability statement

Data will be made available by the corresponding author upon request.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.