TY - JOUR
T1 - The tumour suppressor protein, p53, is involved in the activation of the apoptotic cascade by Δ9-tetrahydrocannabinol in cultured cortical neurons
AU - Downer, Eric J.
AU - Gowran, Aoife
AU - Murphy, Áine C.
AU - Campbell, Veronica A.
PY - 2007/6/14
Y1 - 2007/6/14
N2 - Cannabis is the most commonly used illegal drug of abuse in Western society. Δ9-tetrahydrocannabinol, the psychoactive ingredient of marijuana, regulates a variety of neuronal processes including neurotransmitter release and synaptic transmission. An increasing body of evidence suggests that cannabinoids play a key role in the regulation of neuronal viability. In cortical neurons tetrahydrocannabinol has a neurodegenerative effect, the mechanisms of which are poorly understood, but involve the cannabinoid receptor subtype, CB1. In this study we report that tetrahydrocannabinol (5 μM) evokes a rapid phosphorylation, and thus activation, of the tumour suppressor protein, p53, in a manner involving the cannabinoid CB1 receptor, and the stress-activated protein kinase, c-jun N-terminal kinase, in cultured cortical neurons. Tetrahydrocannabinol increased expression of the p53-transcriptional target, Bax and promoted Bcl phosphorylation. These events were abolished by the p53 inhibitor, pifithrin-α (100 nM). The tetrahydrocannabinol-induced activation of the pro-apoptotic cysteine protease, caspase-3, and DNA fragmentation was also blocked by pifithrin-α. A siRNA knockdown of p53 further verified the role of p53 in tetrahydrocannabinol-induced apoptosis. This study demonstrates a novel cannabinoid signalling pathway involving p53 that culminates in neuronal apoptosis.
AB - Cannabis is the most commonly used illegal drug of abuse in Western society. Δ9-tetrahydrocannabinol, the psychoactive ingredient of marijuana, regulates a variety of neuronal processes including neurotransmitter release and synaptic transmission. An increasing body of evidence suggests that cannabinoids play a key role in the regulation of neuronal viability. In cortical neurons tetrahydrocannabinol has a neurodegenerative effect, the mechanisms of which are poorly understood, but involve the cannabinoid receptor subtype, CB1. In this study we report that tetrahydrocannabinol (5 μM) evokes a rapid phosphorylation, and thus activation, of the tumour suppressor protein, p53, in a manner involving the cannabinoid CB1 receptor, and the stress-activated protein kinase, c-jun N-terminal kinase, in cultured cortical neurons. Tetrahydrocannabinol increased expression of the p53-transcriptional target, Bax and promoted Bcl phosphorylation. These events were abolished by the p53 inhibitor, pifithrin-α (100 nM). The tetrahydrocannabinol-induced activation of the pro-apoptotic cysteine protease, caspase-3, and DNA fragmentation was also blocked by pifithrin-α. A siRNA knockdown of p53 further verified the role of p53 in tetrahydrocannabinol-induced apoptosis. This study demonstrates a novel cannabinoid signalling pathway involving p53 that culminates in neuronal apoptosis.
KW - Apoptosis
KW - p53
KW - Tetrahydrocannabinol
UR - http://www.scopus.com/inward/record.url?scp=34250687550&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34250687550&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2007.02.025
DO - 10.1016/j.ejphar.2007.02.025
M3 - Article
C2 - 17379209
AN - SCOPUS:34250687550
VL - 564
SP - 57
EP - 65
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1-3
ER -