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Piperlongumine targets NF-κB and its downstream signaling pathways to suppress tumor growth and metastatic potential in experimental colon cancer

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Abstract

NF-κB is the principle transcription factor and plays the central role in orchestrating chronic inflammation by regulating levels of cytokines, chemokines and growth factors. Piperlongumine (PL), a major alkaloid in the fruit of Piper longum Linn. has gained worldwide attention for its anticancer properties, however, its mechanism of action in the chemoprevention of colon cancer has not been investigated yet. Therefore, the present study was designed to elucidate the underlying molecular mechanism of PL in preventing DMH/DSS induced experimental colon cancer in mice. In the current study well established DMH/DSS induced experimental colon cancer mouse model was used to demonstrate the chemopreventive potential of PL. The expression of NF-κB and its downstream target proteins was evaluated mainly through western blotting. In addition, CAM assay, immunohistochemical staining and gelatin zymography was used to show anti-angiogenic and anti-invasive potential of PL. Additionally, important tumor biomarkers such as TSA, LASA, LDH and IL-6 levels were also estimated. The results of current study showed that PL was capable to inhibit NF-κB activation as well as its nuclear translocation. PL administration to DMH/DSS treated mice also inhibited the NF-κB downstream signaling cascades such as including COX-2 pathway, JAK/STAT pathway, β-catenin, Notch signaling pathway, angiogenesis and epithelial to mesenchymal transition pathway. The findings of the present study have claimed PL as promising chemopreventive agent for colon cancer with pleiotropic action. The current study emphasizes that regular consumption of PL can be an effective approach in the prevention of colon cancer in humans.

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Abbreviations

AB:

Alcian blue

APC:

Adenomatous polyposis coli

COX-2:

Cyclooxygenase 2

DMH:

1,2-Dimethylhydrazine

DMSO:

Dimethylsulfoxide

DSS:

Dextran sulphate sodium salt

EDTA:

Ethylenediaminetetraacetic acid

EMT pathway:

Epithelial to mesenchymal transition pathway

GSK3β:

Glycogen synthase kinase-3β

HES:

Hairy/enhancer of split

HEY:

Hairy/enhancer-of-split related with YRPW motif protein 1

IKK:

IκB kinase

IκBα:

Inhibitory kappa Bα

JAK2:

Janus kinase 2

LASA:

Lipid associated sialic acid

LDH:

Lactate dehydrogenase

MMPs:

Matrix metalloproteinases

NF-κB:

Nuclear factor kappa B

NSAIDs:

Nonsteroidal anti-inflammatory drugs

PAS:

Periodic-acid-Schiff

PGDS:

Prostaglandin D2 synthase

PGES:

Prostaglandin E synthase

PMSF:

Phenylmethylsulfonyl fluoride

STAT3:

Signal transducer and activator of transcription3

TCF/ZEB:

T cell factor/zinc finger E-box-binding homeobox protein

TSA:

Total sialic acid

VEGF:

Vascular endothelial growth factor

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Acknowledgements

The authors acknowledge the assistance from the University Grants Commission (UGC), New Delhi, India, as the department is supported under the UGC SAP program. Sandeep Kumar thanks UGC, New Delhi, for providing Senior Research Fellowship to carry out the research work.

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  1. Department of Biochemistry, Basic Medical Science, Block-II, Sector-25, South Campus, Panjab University, Chandigarh, 160014, India

    Sandeep Kumar & Navneet Agnihotri

  2. Pharmacology and Toxicology Lab, Block J, CSIR-IHBT, Palampur, Himachal Pradesh, 176061, India

    Sandeep Kumar

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Kumar, S., Agnihotri, N. Piperlongumine targets NF-κB and its downstream signaling pathways to suppress tumor growth and metastatic potential in experimental colon cancer. Mol Cell Biochem 476, 1765–1781 (2021). https://doi.org/10.1007/s11010-020-04044-7

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