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The dietary flavonoid apigenin enhances the activities of the anti-metastatic protein CD26 on human colon carcinoma cells

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Abstract

There is accumulating evidence that secondary plant metabolites such as flavonoids may have anti-cancer properties, and yet the molecular pathways that lead to alterations in cancer cell behaviour remain unclear. We investigated the possible actions of apigenin, a flavone present in leafy vegetables like parsley, on the levels of CD26 in carcinoma cells. CD26 is a multifunctional cell-surface protein that through its associated dipeptidyl peptidase (DPPIV) and ecto-adenosine deaminase (eADA) enzyme activities is able to suppress pathways involved in tumour metastasis. CD26 is down-regulated in various cancers including colorectal carcinoma. Apigenin substantially up-regulated cell-surface CD26 on HT-29 and HRT-18 human colorectal cancer cells. Levels of CD26 protein, along with its associated DPPIV enzyme activity, capacity to bind eADA, and ability to link cells to fibronectin, were increased with a maximum after 24–48 h. Elevation of CD26 occurred at concentrations that were at least 10-fold less than those shown to affect cell growth, and 100-fold below those that could affect cell viability. Furthermore, the CD26 effect was enhanced when apigenin was paired with chemotherapeutic agents utilized in the treatment of advanced colorectal cancer including irinotecan, 5-fluorouracil and oxaliplatin. For irinotecan, apigenin caused a 4-fold increase in the potency of the drug. These results demonstrate that apigenin can increase the cellular levels of CD26 and its multiple functions, and may oppose the predicted effect of decreased DPPIV and eADA activities on carcinoma cells, which is to facilitate tumour growth and metastasis.

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Abbreviations

5-FU:

5-Fluorouracil

A-7-O-N:

Apigenin-7-O-neohesperidoside, rhoifolin

ADA:

Adenosine deaminase

ANOVA:

Analysis of variance

BSA:

Bovine serum albumin

CXCL12:

Stromal-derived factor-1, SDF-1α

DMEM:

Dulbecco’s modified Eagles medium

DMSO:

Dimethyl sulfoxide

DPPIV:

Dipeptidyl peptidase IV

eADA:

Ecto-adenosine deaminase

ECM:

Extracellular matrix

EDTA:

Ethylenediamine tetraacetic acid

FAP-α:

Fibroblast activated protein-alpha

FN:

Fibronectin

HIV:

Human immunodeficiency virus

IT:

Irinotecan

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NCS:

Newborn calf serum

OX:

Oxaliplatin

PBS:

Phosphate-buffered saline

SDH:

Succinate dehydrogenase

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Acknowledgments

This work was supported by grants from the Canadian Institutes for Health Research (CIHR) and Natural Sciences and Engineering Research Council of Canada (NSERC) awarded to Dr. J. Blay. É.C. Lefort was supported by a CRTP studentship award from the Beatrice Hunter Cancer Research Institute (BHCRI). JB is a Senior Scientist of the BHCRI.

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Authors and Affiliations

  1. Department of Pathology, Dalhousie University, Halifax, NS, B3H 1X5, Canada

    Émilie C. Lefort & Jonathan Blay

  2. Department of Pharmacology, Faculty of Medicine, Dalhousie University, Sir Charles Tupper Building, Halifax, NS, B3H 1X5, Canada

    Jonathan Blay

  3. Department of Biology, Dalhousie University, Halifax, NS, B3H 1X5, Canada

    Jonathan Blay

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  1. Émilie C. Lefort
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Correspondence to Jonathan Blay.

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Lefort, É.C., Blay, J. The dietary flavonoid apigenin enhances the activities of the anti-metastatic protein CD26 on human colon carcinoma cells. Clin Exp Metastasis 28, 337–349 (2011). https://doi.org/10.1007/s10585-010-9364-6

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