Modulation of <i>PI3K</i> / <i>AKT</i> / <i>mTOR</i> and apoptosis pathway in colon cancer cells by the plant flavonoid fisetin

Colorectal cancer (CRC) is a complex multifactorial disease caused by genetic and epigenetic changes playing a vital role in its development and progression. Chemotherapy remains a major option in the treatment of CRC. However, due to its unintended effects on normal tissue, research on identifying plant-based therapeutic agents as an alternative treatment modality has gained attention. Fisetin, a plant-derived flavonoid, has shown promising effects as an anticancer agent against several human cancers, including colon cancer. However, there is limited research focusing on studying the mechanism of action of fisetin. The <i>PI3K</i>/<i>AKT</i>/<i>mTOR</i> pathway as a key regulator of cancer cells has become a promising target for potential anti-cancer development. This study examined the anti-cancer effects of fisetin, emphasizing its effects on the <i>PI3K</i>/<i>AKT</i>/<i>mTOR</i> and apoptosis pathways in human colon cancer Caco-2 cells. The Caco-2 cells were treated with different concentrations (15, 30, 60, 90, or 120 µM) of fisetin for 12 or 24 h. Cell viability was evaluated using the MTT assay, while the expressions of <i>PI3K</i>/<i>AKT</i>/<i>mTOR</i> pathway genes and apoptosis genes, <i>BAX</i> and <i>BCL-2</i>, were analyzed by qRT-PCR. Fisetin markedly decreased the cell viability in a dose- and time-dependent manner. Fisetin down-regulated <i>BCL-2</i>, <i>PI3K</i>, <i>mTOR</i>, and <i>NF</i>-<i>κB</i> gene expression while up-regulating <i>BAX</i> gene expression. This suggested the inhibition of <i>PI3K</i>/<i>AKT</i>/<i>mTOR</i> pathway and induction of apoptosis. GeneMANIA and OncoDB further corroborated these results. These data demonstrate that the antiproliferative effects of fisetin were medicated through the modulation of <i>PI3K</i>/<i>AKT</i>/<i>mTOR</i> and apoptosis pathway. Thus, the study underscores fisetin's potential as a cancer-preventative drug against cancer.