The critical role of the phytosterols in modulating tumor microenvironment via multiple signaling: A comprehensive molecular approach

Abstract

Cancer is the leading cause of mortality and morbidity worldwide, and its cases are rapidly increasing every year. Several factors contribute to the development of tumorigenesis. including radiation, dietary lifestyle, smoking, environmental, and genetic factors. The cell cycle is regulated by a variety of molecular signaling proteins. However, when the proteins involved in the cell cycle regulation are altered, cellular growth and proliferation are significantly affected. Natural products provide an important source of new drug development for a variety of ailments. including cancer. Phytosterols (PSs) are an important class of natural compounds reported for numerous pharmacological activities, including cancer. Various PSs, such as ergosterol, stigmasterol, sitosterol, withaferin A, etc., have been reported for their anti‐cancer activities against a variety of cancer by modulating the tumor microenvironment via molecular signaling pathways discussed within the article. These signaling pathways are associated with the production of pro‐inflammatory mediators, growth factors, chemokines, and pro‐apoptotic and anti‐apoptotic genes. These mediators and their upstream signaling are very active within the variety of tumors and by modulating these signalings, thus PS exhibits promising anti‐cancer activities. However, further high‐quality studies are needed to firmly establish the clinical efficacy as well the safety of the phytosterols.

Antiproliferative Effect of 7- Ketositosterol in Breast and Liver Cancer Cells: Possible Impact of Ceramide, ERK and NF-kB Signaling Pathways

“…Different phytosterols have been described for their antitumor actions by preventing NF-κB activation and decreasing inflammatory cytokines and chemokines focusing on NF-κB signaling [16]. NF-κB p65, a transcription factor, possesses signals for nuclear localization, regions for binding to DNA, and two activation domains known as TA1 and TA2.…”

“…Extracellular signal-regulated kinases (ERK), also known as mitogen-activated protein kinases (MAPK), show an important function in cancer pathogenesis [15]. Phytosterols have been clearly recognized in the regulation of ERK signaling [16]. It is also known that ceramide inhibits ERKs consisting of ERK1 and ERK2 [17].…”

“…Nuclear Factor kappa B (NF-κB) and ERKs are described to adjust the expression of the cell cycle genes causing an increase in cell growth, proliferation, and angiogenesis [19]. Numerous phytosterols inhibit tumor growth and diminish the tumor microenvironment by preventing the activation of the NF-kB and ERK signaling, as well as production of cytokines [16].…”

The Inhibitory Effects and Cytotoxic Activities of the Stem Extract of Nepenthes miranda against Single-Stranded DNA-Binding Protein and Oral Carcinoma Cells

“…In this study, the most abundant compound in the stem extract of N. miranda analyzed via GC-MS was plumbagin (12.9%), and, thus, the cytotoxic properties of this extract against Ca9-22 cells may be related to plumbagin. In addition, sitosterol, a phytosterol possessing significant anticancer activities against a variety of cancers [50,51], was the second most abundant compound (6.5%) found in the stem extract of N. miranda. Accordingly, the stem extract of N. miranda might induce apoptosis and cause cancer cell death mainly via the co-activities of plumbagin and sitosterol.…”

Chemopreventive Effect of an In Vitro Digested and Fermented Plant Sterol-Enriched Wholemeal Rye Bread in Colon Cancer Cells

“…The chemopreventive effect is mediated by apoptosis induction and cell cycle regulation of tumoral cells, via NF-κB inhibition, or a decrease in gene expression of Bcl-2 and cyclin D1, among others. This action is attributed to their low intestinal absorption [ 9 , 10 ]. In this sense, previous studies have assessed the chemopreventive effect of estimated colonic concentrations of various PSs [ 11 , 12 ], and of PS-enriched beverages [ 13 ].…”