Indicaxanthin Induces Autophagy in Intestinal Epithelial Cancer Cells by Epigenetic Mechanisms Involving DNA Methylation

Abstract

Autophagy is an evolutionarily conserved process critical in maintaining cellular homeostasis. Recently, the anticancer potential of autophagy inducers, including phytochemicals, was suggested. Indicaxanthin is a betalain pigment found in prickly pear fruit with antiproliferative and pro-apoptotic activities in colorectal cancer cells associated with epigenetic changes in selected methylation-silenced oncosuppressor genes. Here, we demonstrate that indicaxanthin induces the up-regulation of the autophagic markers LC3-II and Beclin1, and increases autophagolysosome production in Caco-2 cells. Methylomic studies showed that the indicaxanthin-induced pro-autophagic activity was associated with epigenetic changes. In addition to acting as a hypermethylating agent at the genomic level, indicaxanthin also induced significant differential methylation in 39 out of 47 autophagy-related genes, particularly those involved in the late stages of autophagy. Furthermore, in silico molecular modelling studies suggested a direct interaction of indicaxanthin with Bcl-2, which, in turn, influenced the function of Beclin1, a key autophagy regulator. External effectors, including food components, may modulate the epigenetic signature of cancer cells. This study demonstrates, for the first time, the pro-autophagic potential of indicaxanthin in human colorectal cancer cells associated with epigenetic changes and contributes to outlining its potential healthy effect in the pathophysiology of the gastrointestinal tract.

Osteoarthritis in the Elderly Population: Preclinical Evidence of Nutrigenomic Activities of Flavonoids

“…Recently, treatment strategies for OA have been developed that target senescent cells and the paracrine and autocrine secretions of the senescence-associated secretory phenotype [ 102 ]. Our labs have already ascertained the nutrigenomic effects of some molecules contained in plants, highlighting their effects on inflammation and autophagy, and their power to counteract epi-mutagenic actions [ 90 , 103 , 104 , 105 , 106 ], for example, arsenic-induced actions [ 106 ]. We therefore believe that the nutrigenomic approach represents the most modern frontier for understanding the action of flavonoids in OA.…”

Drought-Adapted Mediterranean Diet Plants: A Source of Bioactive Molecules Able to Give Nutrigenomic Effects per sè or to Obtain Functional Foods

“…The same is said of Indicaxanthin, where we note its properties as a redox agent [26], as a protector against hemolysis [27], and as a pigment capable of crossing the blood-brain barrier when administered in nutritionally relevant quantities [28]. Recent studies have also shown the role of indicaxanthin as a modulator of DNA methylation in Caco2 cells, making this molecule a good candidate for an anticancer drug [12], and its pro-autophagic potential in human colorectal cancer cells [29].…”