Aspirin blocks proliferation of colorectal cancer cells and causes them to self destruct by inhibiting the mechanistic target of rapamycin (mTOR), according to the June issue of Gastroenterology.
Aspirin is a nonsteroidal anti-inflammatory drug that has been shown in many studies to reduce risk of cancer—particularly of CRC—by unknown mechanisms.
Many signaling pathways are dysregulated in cancer cells, including phosphoinositide-3-kinase (PI3K) signaling via mechanistic target of rapamycin (mTOR)—a serine/threonine kinase that controls cell survival and regulates cell metabolism. mTOR is overexpressed in colorectal cancer cells, and PTEN, which down-regulates mTOR, is inactivated in 30%–40% of colorectal tumors.
Farhat Din et al. therefore investigated the effects of aspirin on mTOR activity. They found that aspirin inhibited mTOR signaling in colorectal cancer cells by activating adenosine monophosphate–activated protein kinase (AMPK), a suppressor of mTOR.
mTOR is a negative regulator of a cell self-destruction process called autophagy. Din et al. also found that aspirin induced autophagy in colorectal cancer cells, probably through AMPK-mediated phosphorylation of ULK1 and inhibition of mTOR (see figure).
But does aspirin have the same effects in vivo that it has in cultured cancer cells? Din et al. found that administration of aspirin to mice activated AMPK in colon tissues. Then, they gave patients 600 mg aspirin, orally once daily for 7 days, and collected rectal mucosa samples at different timepoints during treatment. They found that the activities of mTOR were reduced in patients that took the aspirin.
Clinical trials of mTOR-specific inhibitors have been disappointing, especially for solid tumors. Studies of rapamycin, which specifically binds and inhibits mTOR, showed that a feedback loop counters mTOR inhibition. Furthermore, the long-term safety profile of mTOR-specific inhibitors is unknown, and so their use for cancer chemoprevention is not appropriate.
Din et al. propose that aspirin acts on several different cellular pathways, and that the nonspecific nature of its effects could be the key to cancer prevention. Further studies are needed to determine the complex effects of aspirin on cancer cells.
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Din FVN, Valanciute A, Houde VP, et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 2012;142:1504-1515.e3.