27-hydroxycholesterol decreases cell proliferation in colon cancer cell lines

Abstract

Colorectal cancer (CRC) is the third most diagnosed cancer in the western world, affecting 1 out of approximately 22 people in their lifetime. Several epidemiological studies suggest a positive association between high plasma cholesterol levels and colorectal cancer. However, the molecular mechanisms by which cholesterol may alter the risk of colorectal cancer (CRC) are ill-defined as the cholesterol lowering drugs statins do not appear to decrease a patient's risk of developing colorectal cancer. Cholesterol is metabolized to active derivatives including cholesterol oxidization products (COP), known as oxysterols, which have been shown to alter cellular proliferation. These metabolites and not cholesterol per se, may therefore affect the risk of developing colorectal cancer. The cholesterol metabolite or the oxysterol 27-hydroxycholesterol (27-OHC) is the most abundant oxysterol in the plasma and has been shown to be involved in the pathogenesis of several cancers including breast and prostate cancer. However, the role of 27-OHC in colorectal cancer has not been investigated. We treated Caco2 and SW620, two well characterized colon cancer cells with low, physiological and high concentrations of 27-OHC, and found that 27-OHC reduces cellular proliferation in these cells. We also found that the effects of 27-OHC on cell proliferation are not due to cellular cytotoxicity or apoptotic cellular death. Additionally, 27-OHC-induced reduction in cell proliferation is independent of actions on its target nuclear receptors, liver-X-receptors (LXR) and estrogen receptors (ER) activation. Instead, our study demonstrates that 27-OHC significantly decreases AKT activation, a major protein kinase involved in the pathogenesis of cancer as it regulates cell cycle progression, protein synthesis, and cellular survival. Our data shows that treatment with 27-OHC substantially decreases the activation of AKT by reducing levels of its active form, p-AKT, in Caco2 cells but not SW620 cells. All-together, our results show for the first time that the cholesterol metabolite 27-OHC reduces cell proliferation in colorectal cancer cells.

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

“…Indeed, 27HC together with 24(R/S), 25-epoxycholesterol dampens gastric cancer cell proliferation and migration via modulation of LXR signaling 57 . Similarly, 27HC treatment impedes cell proliferation in colorectal cancer cells, but this effect is mediated by decreased activating phosphorylation of the kinase Akt rather than LXR activation 58 . In addition to 27HC, other oxysterols such as 7-ketocholesterol, cholestane-3β-5α-6β-triol and 5α-cholestane-3β,6β-diol can impede cell-cycle progression and trigger apoptosis in multiple human and mouse cancer cell lines 59 .…”

Increased production of 27-hydroxycholesterol in human colorectal cancer advanced stage: Possible contribution to cancer cell survival and infiltration

“…The interplay among different pro-inflammatory molecules induced by 27HC in micromolar amount might contribute to the survival signaling pathway activation, an important mechanism promoting tumor resistance against apoptosis. Such [33]. Those findings were actually obtained by using undifferentiated intestinal cancer cells, thus introducing even higher intercellular variability and higher 27HC concentrations (from 10 µM upward).…”

Diverse Immunoregulatory Roles of Oxysterols—The Oxidized Cholesterol Metabolites

“…Moreover, accumulated levels of 27-HC were found in human gastric tumour tissues and were reported to decrease gastric cancer cell proliferation and migration by modulating LXR signalling [ 106 ]. Similarly, 27-HC was reported to inhibit colorectal cancer cell proliferation independently of ER or LXR signalling but rather through decreasing Akt activation [ 107 ]. Collectively, the direct actions of oxysterols upon cancer cells are varied and need further investigation.…”