Genistein exerts anti-colorectal cancer actions: clinical reports, computational and validated findings

Abstract

Colorectal cancer (CRC) is presently a health challenge in China. Although clinical chemotherapy is prescribed availably, the negative effects and poor prognoses still occur. Genistein has antitumor properties in our previous studies. However, the molecular mechanisms underlying the anti-CRC effects of genistein remain unclear. Increasing evidences have indicated that the induction of autophagy, one of cell death models, is closely associated with the formation and development of human cancer. In the current study, a systematic bioinformatics approach using network pharmacology and molecular docking imitation was aimed at identifying the pharmacological targets and anti-CRC mechanisms of genistein, characterized by autophagy-related processes and pathways. Moreover, experimental validation was conducted by using clinical and cell culture samples. All 48 potential targets of genistein-anti-CRC-associated autophagy were screened accordingly. Further bioinformatics analyses identified 10 core genistein-anti-CRC targets related to autophagy, and enrichment-assayed results revealed that the biological processes of these core targets might regulate multiple molecular pathways, including the estrogen signaling pathway. Additionally, molecular docking data demonstrated that genistein has a high affinity for epidermal growth factor receptor (EGFR) and estrogen receptor 1 (ESR1). Both EGFR and ESR1 proteins were highly expressed in clinical CRC samples. Preliminary in vitro data showed that genistein effectively reduced cellular proliferation, activated apoptosis, and suppressed EGFR and ESR1 protein expressions in CRC cells. Our research findings uncovered the molecular mechanisms of genistein against CRC, and the potential drug targets associated with autophagy in genistein treatment of CRC were identified and validated experimentally, including EGFR and ESR1.

Natural polyphenols: A protective approach to reduce colorectal cancer

“… By inducing apoptosis, initiating cell cycle arrest, and decreasing angiogenesis, metastasis, and cell proliferation [ 122 ] 8 Anthocyanins Anthocyanins avoid metastasis and inhibit cell growth by acting on Ras-MAPK and PI3K/Akt signal cascade pathways Anthocyanins can act indirectly or directly by targeting multiple signaling pathways leading to CRC development, therefore inducing apoptosis and cell cycle arrest, and blocking cell migration, metastasis, and uncontrolled inflammation and oxidative stress. [ 123 ] 9 Genistein inhibit colon cancer via the PI3K/Akt pathway Genistein exerts potential antimetastatic CRC benefits, presumably by blocking the PI3K/Akt in CRC cells through a molecular mechanism [ 124 ] 10 Capsaicin The TRVP1 agonist capsaicin inhibit CRC growth by activating P53 Overexpression of TRPV1 by capsaicin treatment could inhibit cell and increase cell apoptosis in HCT116 cells through activating p53. [ 62 ] …”

Molecular Pathways of Genistein Activity in Breast Cancer Cells

“…Several studies supporting the multi-target mechanism of genistein's anti-tumor activities have been conducted [66][67][68][69][70][71][72][73][74]. Cell cycle regulation [75,76], tyrosine kinases [77], DNA topoisomerases [78], telomerase [79], apoptosis [80], and angiogenesis [81] have all been found to be inhibited by genistein.…”

Genistein–Aspirin Combination Exerts Cytotoxic and Anti-Migratory Effects in Human Colorectal Cancer Cells

“…This natural compound possesses various biological effects; it is antioxidant, anti-inflammatory, antiangiogenic, protective against osteoporosis, decreases the risk of cardiovascular pathology, palliates postmenopausal symptoms, and promotes anticancer activity [10]. With regard to GEN's impact in CRC, a number of preclinical studies described several mechanisms of action, such as (i) a decrease in cellular proliferation, induction of apoptosis, and suppression of the epidermal growth factor receptor (EGFR), as well as of estrogen receptor 1 (ESR1) expressions in colorectal cancer cells (HCT-116) [11]; (ii) inhibition of HCT-116 cells proliferation, inhibition of apoptosis, down-regulation of Akt, SGK1 and miR-95 mRNA expressions, and suppression of tumor growth in vivo [12]; (iii) inhibition of colon cancer cells' (HT-29) migration by reversing epithelial-to-mesenchymal transition via suppression of the Notch1/NF-κB/slug/E-cadherin pathway [13]; (iv) induction of apoptosis in colorectal cancer cell lines SW480 and SW620 by stimulating the oxidative reactive species (ROS) production [14]; and (v) suppression of colon cancer cells' (HT-29) invasion and migration via demethylation and modulation of Wnt signaling pathway [15].…”