Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells

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Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. / Din, Farhat V.N.; Valanciute, Asta; Houde, Vanessa P.; Zibrova, Daria; Green, Kevin A.; Sakamoto, Kei; Alessi, Dario R.; Dunlop, Malcolm G.

In: Gastroenterology, Vol. 142, No. 7, 06.2012, p. 1504-1515.e3.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Din, FVN, Valanciute, A, Houde, VP, Zibrova, D, Green, KA, Sakamoto, K, Alessi, DR & Dunlop, MG 2012, 'Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells', Gastroenterology, vol. 142, no. 7, pp. 1504-1515.e3. https://doi.org/10.1053/j.gastro.2012.02.050

APA

Din, F. V. N., Valanciute, A., Houde, V. P., Zibrova, D., Green, K. A., Sakamoto, K., Alessi, D. R., & Dunlop, M. G. (2012). Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology, 142(7), 1504-1515.e3. https://doi.org/10.1053/j.gastro.2012.02.050

Vancouver

Din FVN, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology. 2012 Jun;142(7):1504-1515.e3. https://doi.org/10.1053/j.gastro.2012.02.050

Author

Din, Farhat V.N. ; Valanciute, Asta ; Houde, Vanessa P. ; Zibrova, Daria ; Green, Kevin A. ; Sakamoto, Kei ; Alessi, Dario R. ; Dunlop, Malcolm G. / Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. In: Gastroenterology. 2012 ; Vol. 142, No. 7. pp. 1504-1515.e3.

Bibtex

@article{afdc586e9936495e85e01d545851c719,
title = "Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells",
abstract = "Background & Aims: Aspirin reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether aspirin affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells. Methods: The effects of aspirin on mTOR signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of AMPK was measured; the effects of loss of AMPKα on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPKα1/α2-/- mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg aspirin, once daily for 1 week. Results: Aspirin reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors S6K1 and 4E-BP1. Aspirin changed nucleotide ratios and activated AMPK in CRC cells. mTOR was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPKα, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR. Aspirin induced autophagy, a feature of mTOR inhibition. Aspirin and metformin (an activator of AMPK) increased inhibition of mTOR and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given aspirin had reduced phosphorylation of S6K1 and S6. Conclusions: Aspirin is an inhibitor of mTOR and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC.",
keywords = "Chemoprevention, Colon Cancer, Oncogene, Tumor Suppressor",
author = "Din, {Farhat V.N.} and Asta Valanciute and Houde, {Vanessa P.} and Daria Zibrova and Green, {Kevin A.} and Kei Sakamoto and Alessi, {Dario R.} and Dunlop, {Malcolm G.}",
year = "2012",
month = jun,
doi = "10.1053/j.gastro.2012.02.050",
language = "English",
volume = "142",
pages = "1504--1515.e3",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "Elsevier",
number = "7",

}

RIS

TY - JOUR

T1 - Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells

AU - Din, Farhat V.N.

AU - Valanciute, Asta

AU - Houde, Vanessa P.

AU - Zibrova, Daria

AU - Green, Kevin A.

AU - Sakamoto, Kei

AU - Alessi, Dario R.

AU - Dunlop, Malcolm G.

PY - 2012/6

Y1 - 2012/6

N2 - Background & Aims: Aspirin reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether aspirin affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells. Methods: The effects of aspirin on mTOR signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of AMPK was measured; the effects of loss of AMPKα on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPKα1/α2-/- mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg aspirin, once daily for 1 week. Results: Aspirin reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors S6K1 and 4E-BP1. Aspirin changed nucleotide ratios and activated AMPK in CRC cells. mTOR was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPKα, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR. Aspirin induced autophagy, a feature of mTOR inhibition. Aspirin and metformin (an activator of AMPK) increased inhibition of mTOR and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given aspirin had reduced phosphorylation of S6K1 and S6. Conclusions: Aspirin is an inhibitor of mTOR and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC.

AB - Background & Aims: Aspirin reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether aspirin affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells. Methods: The effects of aspirin on mTOR signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of AMPK was measured; the effects of loss of AMPKα on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPKα1/α2-/- mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg aspirin, once daily for 1 week. Results: Aspirin reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors S6K1 and 4E-BP1. Aspirin changed nucleotide ratios and activated AMPK in CRC cells. mTOR was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPKα, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR. Aspirin induced autophagy, a feature of mTOR inhibition. Aspirin and metformin (an activator of AMPK) increased inhibition of mTOR and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given aspirin had reduced phosphorylation of S6K1 and S6. Conclusions: Aspirin is an inhibitor of mTOR and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC.

KW - Chemoprevention

KW - Colon Cancer

KW - Oncogene

KW - Tumor Suppressor

UR - http://www.scopus.com/inward/record.url?scp=84861648941&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2012.02.050

DO - 10.1053/j.gastro.2012.02.050

M3 - Journal article

AN - SCOPUS:84861648941

VL - 142

SP - 1504-1515.e3

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 7

ER -

ID: 239567170