A new study published in the journal Molecular Cell reports that arecoline, an active compound found in areca nuts, has anti-cancer properties.
A ripe areca nut. Image credit: Banni Pulikottil / CC BY 2.5.
Areca nuts are seed of the areca palm (Areca catechu), which grows in Asia, parts of east Africa as well as the tropical Pacific region.
These nuts are chewed for their stimulant effects in many Asian countries, and evidence links the practice to the development of oral and esophageal cancer.
“Observers of health news have complained that coffee, as a widely cited example, is implicated in causing cancer one week and absolved the next. Arecoline (a nicotinic acid-based alkaloid found in areca nuts) is not another instance of the same trend,” said study senior author Prof. Jing Chen, of Emory University School of Medicine and Winship Cancer Institute.
Analogous to nicotine, arecoline was identified as an inhibitor of the mitochondrial acetyl-coenzyme A acetyltransferase 1 (ACAT1), which contributes to the metabolism-distorting Warburg effect in cancer cells.
“This is just a proof of principle, showing that ACAT1 is a good anti-cancer target. We view arecoline as a lead to other compounds that could be more potent and selective,” Prof. Chen said.
He added: “arecoline could be compared to arsenic, a form of which is used as a treatment for acute promyelocytic leukemia, but is also linked to several types of cancer. Plus, arecoline’s cancer-promoting effects may be limited if it is not delivered or absorbed orally.”
“When arecoline first arose in a chemical screen it sounded like a carcinogen to me. But it all depends on the dose and how it is taken into the body.”
The Warburg effect, named after 1931 Nobel laureate Otto Warburg, describes how cancer cells tend to favor the inefficient use of glucose, known as glycolysis, and de-emphasize their mitochondria. Cancer cells benefit from this metabolic distortion because the byproducts of glycolysis can be used as building blocks for fast growth.
Prof. Chen and co-authors had previously identified ACAT1 as a control valve regulating the Warburg effect.
In the current study, they showed that ACAT1 enzymatic activity was higher in several types of cancer cells, even though the levels of ACAT1 protein are about the same.
The reason is that the protein clusters together as tetramers in cancer cells. Tyrosine kinases, often on overdrive in cancer cells, ‘hijack’ ACAT1 and nudge it into tetramers, which are enzymatically more active.
But arecoline can inhibit ACAT1 and prevent it from forming tetramers. This compound forms a chemical bond with part of the ACAT1 protein, the new study showed.
Arecoline appears to do what the researchers proposed it would: it steers cells’ metabolism away from glycolysis.
The compound inhibited the growth of human lung cancer and leukemia cells both in culture and grafted into mice, and did not affect the growth of normal blood cells.
“The enzyme ACAT1 seems to have a double role,” Prof. Chen and co-authors noted.
“It breaks down ketones and the amino acid isoleucine, and it also modifies other proteins through acetylation, which is how it regulates the Warburg effect.”
Genetic mutations in ACAT1 lie behind a very rare metabolic disorder called beta-ketothiolase deficiency.
Complete inhibition of ACAT1 could induce side effects resembling that disorder.
“But when we incompletely ‘knocked down’ ACAT1 in cells using arecoline or genetic tools, the main effect was on protein acetylation, not on ketone metabolism,” Prof. Chen said.
“While we did not see obvious toxicity when treating mice with arecoline, more extensive pharmacokinetic and toxicology studies with arecoline and similar compounds are needed.”
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Jun Fan et al. Tetrameric Acetyl-CoA Acetyltransferase 1 is Important for Tumor Growth. Molecular Cell, published online November 17, 2016; doi: 10.1016/j.molcel.2016.10.014
