Effects of mevalonate kinase interference on cell differentiation, apoptosis, prenylation and geranylgeranylation of human keratinocytes are attenuated by farnesyl pyrophosphate or geranylgeranyl pyrophosphate

Li,Min; Min,Wei; Wang,Jianbo; Wang,Lu; Li,Yan; Zhou,Naihui; Yang,Ziliang; Qian,Qihong

doi:10.3892/etm.2020.8569

Effects of mevalonate kinase interference on cell differentiation, apoptosis, prenylation and geranylgeranylation of human keratinocytes are attenuated by farnesyl pyrophosphate or geranylgeranyl pyrophosphate

Authors:
- Min Li
- Wei Min
- Jianbo Wang
- Lu Wang
- Yan Li
- Naihui Zhou
- Ziliang Yang
- Qihong Qian
View Affiliations

Affiliations: Department of Dermatology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China, Department of Dermatology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, P.R. China
Published online on: February 27, 2020 https://doi.org/10.3892/etm.2020.8569
Pages: 2861-2870
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Mevalonate kinase (MVK) mutations were previously identified in disseminated superficial actinic porokeratosis. However, the role of MVK in differentiation, apoptosis and prenylation of keratinocytes requires further investigation. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) of the mevalonate pathway attach to small G proteins, and serve as molecular switches in biochemical pathways. Therefore, the aim of the present study was to investigate the role of MVK in the expression of keratin 1 and involucrin, apoptosis, protein prenylation and the processing of small G proteins. HaCat human keratinocytes were transfected with viruses carrying MVK interference and overexpression vectors, respectively. The mRNA expression of MVK, keratin 1 and involucrin was detected by reverse transcription‑quantitative PCR. Protein expression of MVK, keratin 1, involucrin, lamin A, HRAS, KRAS, NRAS, Rho E, Rho B, Rho A, RAC1 and cdc42 in HaCat cells was detected by western blotting. The apoptotic rates of HaCat cells and protein prenylation levels were examined by flow cytometry. The expression of MVK in HaCat cells was significantly decreased in the interference groups, and markedly increased in the overexpression group compared with the negative control groups. The mRNA and protein expression levels of keratin 1 and involucrin were significantly decreased following interference of MVK expression, and the decrease was markedly attenuated by FPP. Furthermore, the apoptotic rate was markedly increased following MVK interference, and the increase was significantly attenuated by GGPP. The overexpression of MVK significantly decreased the apoptotic rate of HaCat cells. The prenylation levels after MVK interference was notably decreased, which was markedly attenuated by GGPP. The overexpression of MVK significantly increased the prenylation levels of HaCat cells. FPP or GGPP reversed MVK interference‑induced decrease in geranylgeranylation levels of lamin A, HRAS, KRAS, NRAS, Rho E, Rho B, Rho A, RAC1 and cdc42. In conclusion, MVK interference decreases the expression of differentiation markers, increases apoptosis, and decreases protein prenylation and geranylgeranylation levels in keratinocytes. These changes are attenuated by FPP or GGPP.

View Figures

View References

1	Fu Z, Wang M, Potter D, Miziorko HM and Kim JJ: The structure of a binary complex between a mammalian mevalonate kinase and ATP: Insights into the reaction mechanism and human inherited disease. J Biol Chem. 277:18134–18142. 2002.PubMed/NCBI View Article : Google Scholar
2	Houten SM, Wanders RJ and Waterham HR: Biochemical and genetic aspects of mevalonate kinase and its deficiency. Biochim Biophys Acta. 1529:19–32. 2000.PubMed/NCBI View Article : Google Scholar
3	Bouwstra JA and Ponec M: The skin barrier in healthy and diseased state. Biochim Biophys Acta. 1758:2080–2095. 2006.PubMed/NCBI View Article : Google Scholar
4	Zhao Y, Gartner U, Smith FJ and McLean WH: Statins downregulate K6a promoter activity: A possible therapeutic avenue for pachyonychia congenita. J Invest Dermatol. 131:1045–1052. 2011.PubMed/NCBI View Article : Google Scholar
5	Zhang SQ, Jiang T, Li M, Zhang X, Ren YQ, Wei SC, Sun LD, Cheng H, Li Y, Yin XY, et al: Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis. Nat Genet. 44:1156–1160. 2012.PubMed/NCBI View Article : Google Scholar
6	Shen CS, Tabata K, Matsuki M, Goto T, Yokochi T and Yamanishi K: Premature apoptosis of keratinocytes and the dysregulation of keratinization in porokeratosis. Br J Dermatol. 147:498–502. 2002.PubMed/NCBI View Article : Google Scholar
7	Alaei P, MacNulty EE and Ryder NS: Inhibition of protein prenylation down-regulates signalling by inflammatory mediators in human keratinocytes. Biochem Biophys Res Commun. 222:133–138. 1996.PubMed/NCBI View Article : Google Scholar
8	McTaggart SJ: Isoprenylated proteins. Cell Mol Life Sci. 63:255–267. 2006.PubMed/NCBI View Article : Google Scholar
9	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
10	Xia Z, Tan MM, Wong WW, Dimitroulakos J, Minden MD and Penn LZ: Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells. Leukemia. 15:1398–1407. 2001.PubMed/NCBI View Article : Google Scholar
11	Moravcová M, Libra A, Dvořáková J, Víšková A, Muthný T, Velebný V and Kubala L: Modulation of keratin 1, 10 and involucrin expression as part of the complex response of the human keratinocyte cell line HaCaT to ultraviolet radiation. Interdiscip Toxicol. 6:203–208. 2013.PubMed/NCBI View Article : Google Scholar
12	Ichikawa E, Watanabe S and Takahashi H: Keratin and involucrin expression in discoid lupus erythematosus and lichen planus. Arch Dermatol Res. 289:519–526. 1997.PubMed/NCBI View Article : Google Scholar
13	Poumay Y, Herphelin F, Smits P, De Potter IY and Pittelkow MR: High-cell-density phorbol ester and retinoic acid upregulate involucrin and downregulate suprabasal keratin 10 in autocrine cultures of human epidermal keratinocytes. Mol Cell Biol Res Commun. 2:138–144. 1999.PubMed/NCBI View Article : Google Scholar
14	Ichikawa E, Ohnishi T and Watanabe S: Expression of keratin and involucrin in keratoacanthoma: An immunohistochemical aid to diagnosis. J Dermatol Sci. 34:115–117. 2004.PubMed/NCBI View Article : Google Scholar
15	Ivanova P, Atanasova G, Poumay Y and Mitev V: Knockdown of PKD1 in normal human epidermal keratinocytes increases mRNA expression of keratin 10 and involucrin: Early markers of keratinocyte differentiation. Arch Dermatol Res. 300:139–145. 2008.PubMed/NCBI View Article : Google Scholar
16	Pastar I, Stojadinovic O, Sawaya AP, Stone RC, Lindley LE, Ojeh N, Vukelic S, Samuels HH and Tomic-Canic M: Skin metabolite, farnesyl pyrophosphate, regulates epidermal response to inflammation, oxidative stress, and migration. J Cell Physiol. 231:2452–2463. 2016.PubMed/NCBI View Article : Google Scholar
17	Tricarico PM, Romeo A, Gratton R, Crovella S and Celsi F: Lack of prenylated proteins, autophagy impairment and apoptosis in SH-SY5Y neuronal cell model of mevalonate kinase deficiency. Cell Physiol Biochem. 41:1649–1660. 2017.PubMed/NCBI View Article : Google Scholar
18	Tricarico PM, Marcuzzi A, Piscianz E, Monasta L, Crovella S and Kleiner G: Mevalonate kinase deficiency and neuroinflammation: Balance between apoptosis and pyroptosis. Int J Mol Sci. 14:23274–23288. 2013.PubMed/NCBI View Article : Google Scholar
19	Yanae M, Tsubaki M, Satou T, Itoh T, Imano M, Yamazoe Y and Nishida S: Statin-induced apoptosis via the suppression of ERK1/2 and Akt activation by inhibition of the geranylgeranyl-pyrophosphate biosynthesis in glioblastoma. J Exp Clin Cancer Res. 30(74)2011.PubMed/NCBI View Article : Google Scholar
20	Jurczyluk J, Munoz MA, Skinner OP, Chai RC, Ali N, Palendira U, Quinn JM, Preston A, Tangye SG, Brown AJ, et al: Mevalonate kinase deficiency leads to decreased prenylation of Rab GTPases. Immunol Cell Biol. 94:994–999. 2016.PubMed/NCBI View Article : Google Scholar
21	Munoz MA, Jurczyluk J, Mehr S, Chai RC, Arts RJW, Sheu A, McMahon C, Center JR, Singh-Grewal D, Chaitow J, et al: Defective protein prenylation is a diagnostic biomarker of mevalonate kinase deficiency. J Allergy Clin Immunol. 140:873–875, e876. 2017.PubMed/NCBI View Article : Google Scholar
22	Lacbay CM, Waller DD, Park J, Gómez Palou M, Vincent F, Huang XF, Ta V, Berghuis AM, Sebag M and Tsantrizos YS: Unraveling the Prenylation-cancer paradox in multiple myeloma with novel geranylgeranyl pyrophosphate synthase (GGPPS) inhibitors. J Med Chem. 61:6904–6917. 2018.PubMed/NCBI View Article : Google Scholar
23	Satoh K, Ichihara K, Landon EJ, Inagami T and Tang H: 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors block calcium-dependent tyrosine kinase Pyk2 activation by angiotensin II in vascular endothelial cells. involvement of geranylgeranylation of small G protein Rap1. J Biol Chem. 276:15761–15767. 2001.PubMed/NCBI View Article : Google Scholar
24	Wassmann S, Laufs U, Bäumer AT, Müller K, Konkol C, Sauer H, Böhm M and Nickenig G: Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: Involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol. 59:646–654. 2001.PubMed/NCBI View Article : Google Scholar
25	Waiczies S, Bendix I, Prozorovski T, Ratner M, Nazarenko I, Pfueller CF, Brandt AU, Herz J, Brocke S, Ullrich O and Zipp F: Geranylgeranylation but not GTP loading determines rho migratory function in T cells. J Immunol. 179:6024–6032. 2007.PubMed/NCBI View Article : Google Scholar
26	Kusama T, Mukai M, Tatsuta M, Nakamura H and Inoue M: Inhibition of transendothelial migration and invasion of human breast cancer cells by preventing geranylgeranylation of Rho. Int J Oncol. 29:217–223. 2006.PubMed/NCBI
27	Jiang C, Diao F, Sang YJ, Xu N, Zhu RL, Wang XX, Chen Z, Tao WW, Yao B, Sun HX, et al: GGPP-mediated protein geranylgeranylation in oocyte is essential for the establishment of oocyte-granulosa cell communication and primary-secondary follicle transition in mouse ovary. PLoS Genet. 13(e1006535)2017.PubMed/NCBI View Article : Google Scholar
28	Fuchs D, Berges C, Opelz G, Daniel V and Naujokat C: HMG-CoA reductase inhibitor simvastatin overcomes bortezomib-induced apoptosis resistance by disrupting a geranylgeranyl pyrophosphate-dependent survival pathway. Biochem Biophys Res Commun. 374:309–314. 2008.PubMed/NCBI View Article : Google Scholar
29	Yokoyama K, Zimmerman K, Scholten J and Gelb MH: Differential prenyl pyrophosphate binding to mammalian protein geranylgeranyltransferase-I and protein farnesyltransferase and its consequence on the specificity of protein prenylation. J Biol Chem. 272:3944–3952. 1997.PubMed/NCBI View Article : Google Scholar