Eur Rev Med Pharmacol Sci 2021; 25 (21): 6691-6700

DOI: 10.26355/eurrev_202111_27114

AMP-activated protein kinase contributes to ROS-mediated p53 activation in cisplatin-induced nephrotoxicity

S.-M. Ju, J.S. Bae, B.-H. Jeon

Department of Pathology, College of Korean Medicine, Wonkwang University, Iksandae-ro, Iksan, Jeonbuk, Republic of Korea. jsbae78@wku.ac.kr


OBJECTIVE: Cisplatin is a widely used anticancer drug that provokes various side effects. Nephrotoxicity is one of the well-known major side effects in the chemotherapeutic use of cisplatin. Reactive oxygen species (ROS) and p53 play important roles in cisplatin-induced nephrotoxicity. AMP-activated protein kinase (AMPK) is known to be sensitively activated by ROS and can directly activate p53. The present study investigated the role of AMPK on cisplatin-induced apoptosis in rat renal epithelial NRK-52E cells.

MATERIALS AND METHODS: NRK-52E cells were treated with cisplatin in the absence or presence of specific ROS scavenger and AMPK inhibitor for indicated times under the serum-free condition. The expression and phosphorylation levels of proteins were evaluated by Western blot and densitometry analysis.

RESULTS: Cisplatin induced apoptotic cell death through ROS-mediated p53 activation, which is associated with AMPK activation. AMPK inhibitor suppressed cisplatin-induced p53 activation, as well as AMPK activation. Interestingly, ROS scavenger also diminished cisplatin-induced p53 activation and AMPK activation. Furthermore, cisplatin induced phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which attenuated p53 activation, but did not affect the expression levels of total p53, cleaved caspase-3 and PARP. Meanwhile, inhibition of AMPK induced premature phosphorylation of eIF2α in cisplatin-treated cells.

CONCLUSIONS: Taken together, these suggest that AMPK may be required for activation of p53 by oxidative stress in cisplatin-induced nephrotoxicity. Moreover, eIF2α phosphorylation may interrupt the AMPK-activated p53 in NRK-52E cells exposed to cisplatin, but does not critically affect cisplatin-induced nephrotoxicity because AMPK activation can be disrupted eIF2α phosphorylation.

Free PDF Download

To cite this article

S.-M. Ju, J.S. Bae, B.-H. Jeon
AMP-activated protein kinase contributes to ROS-mediated p53 activation in cisplatin-induced nephrotoxicity

Eur Rev Med Pharmacol Sci
Year: 2021
Vol. 25 - N. 21
Pages: 6691-6700
DOI: 10.26355/eurrev_202111_27114