Inhibition of Cholesterol Esterification Suppresses Growth of Pancreatic Cancer Cells

Raman spectroscopy exploits the inelastic scattering (so-called “Raman” scattering) phenomena to detect spectral signatures of important disease progression biomarkers, including lipids, proteins, and amino acids.

In a paper in the May 2, 2016, online edition of the journal Oncogene the investigators reported finding an aberrant accumulation of cholesteryl esters in human pancreatic cancer specimens and cell lines, mediated by the acyl-CoA cholesterol acyltransferase-1 (ACAT-1) enzyme.

ACAT catalyzes the intracellular esterification of cholesterol and formation of cholesteryl esters. The esterification of cholesterol mediated by ACAT is functionally significant for several reasons. ACAT-mediated esterification of cholesterol limits its solubility in the cell membrane lipids and thus promotes accumulation of cholesterol ester in the fat droplets within cytoplasm; this process is important because the toxic accumulation of free cholesterol in various cell membrane fractions is prevented.

The investigators found that expression of ACAT-1 showed a correlation with poor patient survival. Blocking cholesterol esterification, either by an ACAT-1 inhibitor, such as the drug avasimibe, or by shRNA knockdown, significantly suppressed tumor growth and metastasis in a mouse model of pancreatic cancer. At the molecular level, it was found that ACAT-1 inhibition increased intracellular free cholesterol level, which was associated with elevated endoplasmic reticulum stress and caused apoptosis.

"We show for the first time that if you control the cholesterol metabolism you could reduce pancreatic cancer spread to other organs," said senior author Dr. Ji-Xin Cheng, professor of chemistry and biomedical engineering at Purdue University. "We chose pancreatic cancer to test this approach because it is the most aggressive disease of all the cancers. By using avasimibe, a potent inhibitor of ACAT-1, we found that pancreatic cancer cells were much more sensitive to ACAT-1 inhibition than normal cells. The drug did not induce weight loss, and there was no apparent organ toxicity in the liver, kidney, lung, and spleen."

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