Pitavastatin Induces Apoptosis of Cutaneous Squamous Cell Carcinoma Cells through Geranylgeranyl Pyrophosphate-Dependent c-Jun N-Terminal Kinase Activation.

Content Provider	Europe PMC
Author	Kim, Kyung-Il Kim, Seung-Mee Lee, Young-Yoon Lee, Young Kim, Chang-Deok Yoon, Tae-Jin
Copyright Year	2023
Abstract	BackgroundPitavastatin is a cholesterol-lowering drug and is widely used clinically. In addition to this effect, pitavastatin has shown the potential to induce apoptosis in cutaneous squamous cell carcinoma (SCC) cells.ObjectiveThe purpose of this study is to investigate the effects and possible action mechanisms of pitavastatin.MethodsSCC cells (SCC12 and SCC13 cells) were treated with pitavastatin, and induction of apoptosis was confirmed by Western blot. To examine whether pitavastatin-induced apoptosis is related to a decrease in the amount of intermediate mediators in the cholesterol synthesis pathway, the changes in pitavastatin-induced apoptosis after supplementation with mevalonate, squalene, geranylgeranyl pyrophosphate (GGPP) and dolichol were investigated.ResultsPitavastatin dose-dependently induced apoptosis of cutaneous SCC cells, but the viability of normal keratinocytes was not affected by pitavastatin at the same concentrations. In supplementation experiments, pitavastatin-induced apoptosis was inhibited by the addition of mevalonate or downstream metabolite GGPP. As a result of examining the effect on intracellular signaling, pitavastatin decreased Yes1 associated transcriptional regulator and Ras homolog family member A and increased Rac family small GTPase 1 and c-Jun N-terminal kinase (JNK) activity. All these effects of pitavastatin on signaling molecules were restored when supplemented with either mevalonate or GGPP. Furthermore, pitavastatin-induced apoptosis of cutaneous SCC cells was inhibited by a JNK inhibitor.ConclusionThese results suggest that pitavastatin induces apoptosis of cutaneous SCC cells through GGPP-dependent JNK activation.
ISSN	10139087
Journal	Annals of Dermatology
Volume Number	35
PubMed Central reference number	PMC10112368
Issue Number	2
PubMed reference number	37041705
e-ISSN	20053894
DOI	10.5021/ad.22.139
Language	English
Publisher	The Korean Dermatological Association; The Korean Society for Investigative Dermatology
Publisher Date	2023-04-01
Access Restriction	Open
Rights License	This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © The Korean Dermatological Association and The Korean Society for Investigative Dermatology
Subject Keyword	Apoptosis c-Jun N-terminal kinase Pitavastatin Squamous cell carcinoma cells
Content Type	Text
Resource Type	Article
Subject	Dermatology