BERKELEY, CA (UroToday.com) -
In this report, we demonstrated that atorvastatin induces autophagy through activation of transcription of LC3, which is mediated by Erk and JNK signaling pathways and leads to elevation of LC3-II level. Based on the data, we propose a mechanism by which atorvastatin induces LC3-II expression and activates autophagy. Atorvastatin impairs protein geranylgeranylation, which activates Erk and JNK signaling to promote the transcription of LC3 and leads to elevation of LC3-I protein. LC3-I protein is instantly converted to LC3-II, which results in the activation of the autophagic process in cells. This mechanism differs from the one underlying nutritional stress-induced autophagy. In nutritional stress-induced autophagy, mTOR inactivation is the key event and no translational and transcriptional processes are needed. The differences in the mechanism may be associated with the function: nutritional stress-induced autophagy is for generating nutrients to sustain cell survival, while atorvastatin-induced autophagy may be for initiating the cell death process.
Atorvastatin-induced autophagy is dependent on geranylgeranylation. Our study has shown that the geranylgeranyltransferase (GGTase) I inhibitor GGTI-298, similar to atorvastatin, induces expression of LC3-II in PC3 cells, suggesting that GGTase I-catalyzed geranylgeranylation is involved in atorvastatin-induced autophagy. It has been observed that inactivation of Rho GTPase by lovastatin causes apoptosis in prostate cancer cells derived from transgenic mice with adenocarcinoma of the prostate (TRAMP cells). However, treatment of PC3 cells with the Rho inhibitor C3 ADP-ribosyltransferase or ROCK inhibitor Y27632 did not cause elevation of LC3-II expression, implicating that inactivation of Rho is not the cause for atorvastatin-induced autophagy. Currently, the geranylgeranylated protein(s) mediating the effect of atorvastatin on activation of LC3-II expression has not been identified. It should be noticed that atorvastatin does not elevate expression of LC3-II in androgen receptor-positive prostate cancer LNCaP cells, suggesting that the susceptibility to atorvastatin-induced autophagy is dependent on geranylgeranylation-associated signaling context.
We observed no activation of autophagy induced by nutritional starvation or by inhibition of mTOR in PC3 cells. Although the basal level of LC3, including both LC3-I and LC3-II, in PC3 cells is very low and difficult to detect by immunoblotting, treatment with the lysosomal inhibitor chloroquine rapidly accumulates LC3-II , suggesting that the turnover of autophagosomes is very fast in PC3 cells. This may imply that the nutritional stress-associated autophagic process is constitutively active in PC3 cells, thus is no longer sensitive to the treatment of nutritional starvation. Another interesting observation is that LC3-I level in PC3 cells is very low or undetectable with immunoblotting of the lysates even when LC3-II is significantly elevated by treatment with atorvastatin or chloroquine. This implicates that the conversion of LC3-I to LC3-II is instant in PC3 cells, i.e. the Atg4/Atg7/Atg3-mediated PE ligation process of LC3-I is very active in PC3 cells. The conversion of LC3-I to LC3-II may determine the sensitivity to nutritional stress-induced autophagy. When the conversion of LC3-I to LC3-II is unlimited, the activation of LC3 expression (transcription and translation) may become critical for activation of autophagy.
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Wannian Yang,1 Nicolas Toepfer,2 Chandra Childress,1 Ankur Parikh,2 and Daniel Rukstalis2 as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
1 Weis Center for Research, and 2Department of Urology, Geisinger Clinic, 100 N. Academy Ave., Danville, PA 17822
Atorvastatin induces autophagy in prostate cancer PC3 cells through activation of LC3 transcription - Abstract
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