Abstract
Purpose
As one of the members of the PLC family, the phosphoinositide-specific phospholipase Cε (PLCε) has been shown to play pivotal roles in multiple signal pathways and control a variety of cellular functions. A number of studies have shown that aberrant regulation of PLCε was involved in various types of animal and human cancer. However, the role of PLCε in cancer remains elusive. In this review, we provide an overview of the PLCε, especially its roles in multiple signal pathways, and summarize the recent findings that highlight the roles of PLCε in carcinogenesis and cancer progression, making an avenue to provide a novel therapeutic strategy for the treatment of cancer.
Methods
A literature search mainly paying attention to the network of PLCε involved in tumorigenesis and development was performed in electronic databases.
Results
PLCε plays a key role in medicating the development and progression of human cancers with highest potency to be a target of cancer prevention and treatment.
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Abbreviations
- CICR:
-
Ca2 +-induced Ca2 + release
- DAG:
-
Diacylglycerol
- EGFR:
-
Epidermal growth factor receptor
- FSGS:
-
Focal segmental glomerulosclerosis
- GEF:
-
GTP exchange factor
- GPCRs:
-
G-protein-coupled receptors
- GWAS:
-
Genome-wide association studies
- HNSCC:
-
Head and neck squamous cell carcinoma cells
- IP3:
-
Inositol 1,4,5-trisphosphate
- NS:
-
Nephrotic syndrome
- PCNA:
-
Proliferating cell nuclear antigen
- PH:
-
Pleckstrin homology
- PKC:
-
Protein kinase C
- PKCα:
-
Protein kinase Cα
- PLCε:
-
Phosphoinositide-specific phospholipase Cε
- RA:
-
RAS-associating
- RCC:
-
Renal cell carcinoma
- SCCHN:
-
Squamous cell carcinoma of the head and neck
- VEGF:
-
Vascular endothelial growth factor
References
Abnet CC et al (2010) A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma. Nat Genet 42:764–767. doi:10.1038/ng.649
Ada-Nguema AS, Xenias H, Hofman JM, Wiggins CH, Sheetz MP, Keely PJ (2006) The small GTPase R-Ras regulates organization of actin and drives membrane protrusions through the activity of PLCepsilon. J Cell Sci 119:1307–1319. doi:10.1242/jcs.02835
Amado RG et al (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634
Ardito CM et al (2012) EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22:304–317. doi:10.1016/j.ccr.2012.07.024
Assefa Z, Van Laethem A, Garmyn M, Agostinis P (2005) Ultraviolet radiation-induced apoptosis in keratinocytes: on the role of cytosolic factors. Biochim Biophys Acta 1755:90–106. doi:10.1016/j.bbcan.2005.04.001
Bache KG, Slagsvold T, Stenmark H (2004) Defective downregulation of receptor tyrosine kinases in cancer. EMBO J 23:2707–2712. doi:10.1038/sj.emboj.7600292
Bai Y, Edamatsu H, Maeda S, Saito H, Suzuki N, Satoh T, Kataoka T (2004) Crucial role of phospholipase Cepsilon in chemical carcinogen-induced skin tumor development. Cancer Res 64:8808–8810. doi:10.1158/0008-5472.CAN-04-3143
Bivona TG et al (2003) Phospholipase C gamma activates Ras on the Golgi apparatus by means of RasGRP1. Nature 424:694–698
Boulalas I, Zaravinos A, Karyotis I, Delakas D, Spandidos DA (2009) Activation of RAS family genes in urothelial carcinoma. J Urol 181:2312–2319. doi:10.1016/j.juro.2009.01.011
Bourguignon LY, Gilad E, Brightman A, Diedrich F, Singleton P (2006) Hyaluronan-CD44 interaction with leukemia-associated RhoGEF and epidermal growth factor receptor promotes Rho/Ras co-activation, phospholipase C epsilon-Ca2+ signaling, and cytoskeleton modification in head and neck squamous cell carcinoma cells. J Biol Chem 281:14026–14040. doi:10.1074/jbc.M507734200
Boyer O et al (2010) Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome. J Med Genet 47:445–452. doi:10.1136/jmg.2009.076166
Bunney TD, Katan M (2006) Phospholipase C epsilon: linking second messengers and small GTPases. Trends Cell Biol 16:640–648. doi:10.1016/j.tcb.2006.10.007
Bunney TD, Katan M (2011) PLC regulation: emerging pictures for molecular mechanisms. Trends Biochem Sci 36:88–96. doi:10.1016/j.tibs.2010.08.003
Cheng H et al (2011) shRNA targeting PLCepsilon inhibits bladder cancer cell growth in vitro and in vivo. Urology 78(474):e411–e477
Cho SH, Delehedde M, Rodriguez-Villanueva J, Brisbay S, McDonnell TJ (2001) Bax gene disruption alters the epidermal response to ultraviolet irradiation and in vivo induced skin carcinogenesis. Int J Mol Med 7:235–241
Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867. doi:10.1038/nature01322
Du HF et al (2014) Nuclear factor-kappaB signaling pathway is involved in phospholipase Cepsilon-regulated proliferation in human renal cell carcinoma cells. Mol Cell Biochem 389:265–275. doi:10.1007/s11010-013-1948-4
Dusaban SS, Purcell NH, Rockenstein E, Masliah E, Cho MK, Smrcka AV, Brown JH (2013) Phospholipase C epsilon links G protein-coupled receptor activation to inflammatory astrocytic responses. Proc Natl Acad Sci USA 110:3609–3614. doi:10.1073/pnas.1217355110
Dzhura I et al (2010) Epac2-dependent mobilization of intracellular Ca(2)+ by glucagon-like peptide-1 receptor agonist exendin-4 is disrupted in beta-cells of phospholipase C-epsilon knockout mice. J Physiol 588:4871–4889. doi:10.1113/jphysiol.2010.198424
Eungdamrong NJ, Iyengar R (2007) Compartment-specific feedback loop and regulated trafficking can result in sustained activation of Ras at the Golgi. Biophys J 92:808–815
Geyer CE et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. New Engl J Med 355:2733–2743. doi:10.1056/NEJMoa064320
Greten FR et al (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:285–296. doi:10.1016/j.cell.2004.07.013
Gu H, Ding G, Zhang W, Liu C, Chen Y, Chen S, Jiang P (2012) Replication study of PLCE1 and C20orf54 polymorphism and risk of esophageal cancer in a Chinese population. Mol Biol Rep 39:9105–9111. doi:10.1007/s11033-012-1782-x
He G et al (2010) Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17:286–297. doi:10.1016/j.ccr.2009.12.048
Hicks SN, Jezyk MR, Gershburg S, Seifert JP, Harden TK, Sondek J (2008) General and versatile autoinhibition of PLC isozymes. Mol Cell 31:383–394. doi:10.1016/j.molcel.2008.06.018
Hildesheim J, Bulavin DV, Anver MR, Alvord WG, Hollander MC, Vardanian L, Fornace AJ Jr (2002) Gadd45a protects against UV irradiation-induced skin tumors, and promotes apoptosis and stress signaling via MAPK and p53. Cancer Res 62:7305–7315
Hu H et al (2012) Putatively functional PLCE1 variants and susceptibility to esophageal squamous cell carcinoma (ESCC): a case-control study in eastern Chinese populations. Ann Surg Oncol 19:2403–2410. doi:10.1245/s10434-011-2160-y
Ichinohe M, Nakamura Y, Sai K, Nakahara M, Yamaguchi H, Fukami K (2007) Lack of phospholipase C-delta1 induces skin inflammation. Biochem Biophys Res Commun 356:912–918. doi:10.1016/j.bbrc.2007.03.082
Ikuta S, Edamatsu H, Li M, Hu L, Kataoka T (2008) Crucial role of phospholipase C epsilon in skin inflammation induced by tumor-promoting phorbol ester. Cancer Res 68:64–72. doi:10.1158/0008-5472.CAN-07-3245
Jiang W, Ananthaswamy HN, Muller HK, Kripke ML (1999) p53 protects against skin cancer induction by UV-B radiation. Oncogene 18:4247–4253. doi:10.1038/sj.onc.1202789
Karapetis CS et al (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. New Engl J Med 359:1757–1765. doi:10.1056/NEJMoa0804385
Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–436. doi:10.1038/nature04870
Karin M, Greten FR (2005) NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5:749–759. doi:10.1038/nri1703
Kariya K, Bui YK, Gao X, Sternberg PW, Kataoka T (2004) Phospholipase Cepsilon regulates ovulation in Caenorhabditis elegans. Dev Biol 274:201–210. doi:10.1016/j.ydbio.2004.06.024
Katan M (2005) New insights into the families of PLC enzymes: looking back and going forward. Biochem J 391:e7–e9. doi:10.1042/BJ20051506
Katzmann DJ, Odorizzi G, Emr SD (2002) Receptor downregulation and multivesicular-body sorting. Nat Rev Mol Cell Biol 3:893–905. doi:10.1038/nrm973
Kelley GG, Reks SE, Smrcka AV (2004) Hormonal regulation of phospholipase Cepsilon through distinct and overlapping pathways involving G12 and Ras family G-proteins. Biochem J 378:129–139. doi:10.1042/BJ20031370
Kovacevic I, Cram EJ (2013) Filamin and Phospholipase C-epsilon are required for calcium signaling in the Caenorhabditis elegans. Spermatheca Worm 2:e25717
Lee CH, Wu SB, Hong CH, Yu HS, Wei YH (2013) Molecular mechanisms of UV-induced apoptosis and its effects on skin residential cells: the implication in UV-based phototherapy. Int J Mol Sci 14:6414–6435. doi:10.3390/ijms14036414
Lee JK et al (2014) Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis. Jama 311:1430–1437
Li G, Tron V, Ho V (1998) Induction of squamous cell carcinoma in p53-deficient mice after ultraviolet irradiation. J Invest Dermatol 110:72–75. doi:10.1046/j.1523-1747.1998.00090.x
Li M, Edamatsu H, Kitazawa R, Kitazawa S, Kataoka T (2009) Phospholipase Cepsilon promotes intestinal tumorigenesis of Apc(Min/+) mice through augmentation of inflammation and angiogenesis. Carcinogenesis 30:1424–1432. doi:10.1093/carcin/bgp125
Ling Y, Chunli L, Xiaohou W, Qiaoling Z (2011) Involvement of the PLCepsilon/PKCalpha pathway in human BIU-87 bladder cancer cell proliferation. Cell Biol Int 35:1031–1036. doi:10.1042/CBI20090101
Lopez I, Mak EC, Ding J, Hamm HE, Lomasney JW (2001) A novel bifunctional phospholipase c that is regulated by Galpha 12 and stimulates the Ras/mitogen-activated protein kinase pathway. J Biol Chem 276:2758–2765. doi:10.1074/jbc.M008119200
Ma H, Wang LE, Liu Z, Sturgis EM, Wei Q (2011) Association between novel PLCE1 variants identified in published esophageal cancer genome-wide association studies and risk of squamous cell carcinoma of the head and neck. BMC Cancer 11:258. doi:10.1186/1471-2407-11-258
Malumbres M, Barbacid M (2003) RAS oncogenes: the first 30 years. Nat Rev Cancer 3:459–465. doi:10.1038/nrc1097
Martins M et al (2014) Tumor suppressor role of phospholipase C epsilon in Ras-triggered cancers. Proc Natl Acad Sci USA 111:4239–4244. doi:10.1073/pnas.1311500111
Maung ZT, MacLean FR, Reid MM, Pearson AD, Proctor SJ, Hamilton PJ, Hall AG (1994) The relationship between bcl-2 expression and response to chemotherapy in acute leukaemia. Br J Haematol 88:105–109
Meylan E, Dooley AL, Feldser DM, Shen L, Turk E, Ouyang C, Jacks T (2009) Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma. Nature 462:104–107. doi:10.1038/nature08462
Nagano T et al (2014) Phospholipase cepsilon, an effector of ras and rap small GTPases, is required for airway inflammatory response in a mouse model of bronchial asthma. PLoS ONE 9:e108373. doi:10.1371/journal.pone.0108373
Nakamura Y et al (2008) Phospholipase C-delta1 is an essential molecule downstream of Foxn1, the gene responsible for the nude mutation, in normal hair development. FASEB J 22:841–849
Navas C, Hernandez-Porras I, Schuhmacher AJ, Sibilia M, Guerra C, Barbacid M (2012) EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 22:318–330. doi:10.1016/j.ccr.2012.08.001
Oestreich EA et al (2007) Epac-mediated activation of phospholipase C(epsilon) plays a critical role in beta-adrenergic receptor-dependent enhancement of Ca2+ mobilization in cardiac myocytes. J Biol Chem 282:5488–5495. doi:10.1074/jbc.M608495200
Oka M et al (2010) Enhancement of ultraviolet B-induced skin tumor development in phospholipase Cepsilon-knockout mice is associated with decreased cell death. Carcinogenesis 31:1897–1902. doi:10.1093/carcin/bgq164
Ou L, Guo Y, Luo C, Wu X, Zhao Y, Cai X (2010) RNA interference suppressing PLCE1 gene expression decreases invasive power of human bladder cancer T24 cell line. Cancer Genet Cytogenet 200:110–119. doi:10.1016/j.cancergencyto.2010.01.021
Palmieri D, Bouadis A, Ronchetti R, Merino MJ, Steeg PS (2006) Rab11a differentially modulates epidermal growth factor-induced proliferation and motility in immortal breast cells. Breast Cancer Res Treat 100:127–137. doi:10.1007/s10549-006-9244-6
Pena JC, Rudin CM, Thompson CB (1998) A Bcl-xL transgene promotes malignant conversion of chemically initiated skin papillomas. Cancer Research 58:2111–2116
Ramalingam SS, Owonikoko TK, Khuri FR (2011) Lung cancer: new biological insights and recent therapeutic advances. CA Cancer J Clin 61:91–112. doi:10.3322/caac.20102
Rhee SG (2001) Regulation of phosphoinositide-specific phospholipase C. Annu Rev Biochem 70:281–312. doi:10.1146/annurev.biochem.70.1.281
Rhee SG, Bae YS (1997) Regulation of phosphoinositide-specific phospholipase C isozymes. J Biol Chem 272:15045–15048
Rodriguez-Villanueva J et al (1998) Human keratin-1.bcl-2 transgenic mice aberrantly express keratin 6, exhibit reduced sensitivity to keratinocyte cell death induction, and are susceptible to skin tumor formation. Oncogene 16:853–863. doi:10.1038/sj.onc.1201610
Song C et al (2001) Regulation of a novel human phospholipase C PLCepsilon, through membrane targeting by Ras. J Biol Chem 276:2752–2757
Sorli SC, Bunney TD, Sugden PH, Paterson HF, Katan M (2005) Signaling properties and expression in normal and tumor tissues of two phospholipase C epsilon splice variants. Oncogene 24:90–100. doi:10.1038/sj.onc.1208168
Sun C et al (2014) Reversible and adaptive resistance to BRAF (V600E) inhibition in melanoma. Nature 508:118–122. doi:10.1038/nature13121
Takenaka N et al (2011) Overexpression of phospholipase Cepsilon in keratinocytes upregulates cytokine expression and causes dermatitis with acanthosis and T-cell infiltration. Eur J Immunol 41:202–213. doi:10.1002/eji.201040675
Tran DD, Russell HR, Sutor SL, van Deursen J, Bram RJ (2003) CAML is required for efficient EGF receptor recycling. Dev Cell 5:245–256
Umar S, Sarkar S, Cowey S, Singh P (2008) Activation of NF-kappaB is required for mediating proliferative and antiapoptotic effects of progastrin on proximal colonic crypts of mice, in vivo. Oncogene 27:5599–5611. doi:10.1038/onc.2008.169
Vanags DM, Orrenius S, Aguilar-Santelises M (1997) Alterations in Bcl-2/Bax protein levels in platelets form part of an ionomycin-induced process that resembles apoptosis. Br J Haematol 99:824–831
Vazquez-Manrique RP, Nagy AI, Legg JC, Bales OA, Ly S, Baylis HA (2008) Phospholipase C-epsilon regulates epidermal morphogenesis in Caenorhabditis elegans. PLoS Genet 4:e1000043. doi:10.1371/journal.pgen.1000043
Wang H et al (2005) Phospholipase C epsilon modulates beta-adrenergic receptor-dependent cardiac contraction and inhibits cardiac hypertrophy. Circ Res 97:1305–1313. doi:10.1161/01.RES.0000196578.15385.bb
Wang LD et al (2010) Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and C20orf54. Nat Genet 42:759–763. doi:10.1038/ng.648
Wang LD et al (2013) A sequence variant in the phospholipase C epsilon C2 domain is associated with esophageal carcinoma and esophagitis. Mol Carcinog 52(Suppl 1):E80–E86. doi:10.1002/mc.22016
Wing MR, Snyder JT, Sondek J, Harden TK (2003) Direct activation of phospholipase C-epsilon by Rho. J Biol Chem 278:41253–41258
Xu Z, Wei B, Ruan J, Zhu M, Hu Q, Wang Q, Wang Z (2011) Re: Cheng et al. shRNA targeting PLC inhibits bladder cancer cell growth in vitro and in vivo (Urology 2011;78:474e.7-474e.11) Urology 78:1446–1447. doi:10.1016/j.urology.2011.07.1427
Yun S, Hong WP, Choi JH, Yi KS, Chae SK, Ryu SH, Suh PG (2008) Phospholipase C-epsilon augments epidermal growth factor-dependent cell growth by inhibiting epidermal growth factor receptor down-regulation. J Biol Chem 283:341–349. doi:10.1074/jbc.M704180200
Zhang L, Malik S, Kelley GG, Kapiloff MS, Smrcka AV (2011) Phospholipase C epsilon scaffolds to muscle-specific A kinase anchoring protein (mAKAPbeta) and integrates multiple hypertrophic stimuli in cardiac myocytes. J Biol Chem 286:23012–23021. doi:10.1074/jbc.M111.231993
Zhang L et al (2013a) Phospholipase Cepsilon hydrolyzes perinuclear phosphatidylinositol 4-phosphate to regulate cardiac hypertrophy. Cell 153:216–227. doi:10.1016/j.cell.2013.02.047
Zhang Y, Yan L, Zhao Y, Ou L, Wu X, Luo C (2013b) Knockdown of phospholipase C-epsilon by short-hairpin RNA-mediated gene silencing induces apoptosis in human bladder cancer cell lines Cancer biotherapy & radiopharmaceuticals 28:233–239. doi:10.1089/cbr.2012.1216
Zhou RM, Li Y, Wang N, Liu BC, Chen ZF, Zuo LF (2012) PLC-epsilon 1 gene polymorphisms significantly enhance the risk of esophageal squamous cell carcinoma in individuals with a family history of upper gastrointestinal cancers. Arch Med Res 43:578–584. doi:10.1016/j.arcmed.2012.09.006
Ziegler A et al (1994) Sunburn and p53 in the onset of skin cancer. Nature 372:773–776. doi:10.1038/372773a0
Acknowledgments
This work was supported by the National Natural Science Foundation of China (No. 81372172) and the key project of the Education Department of China (212062) and the Science and Technology Department of Jiangsu Province (BK20130231, BK20141149).
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Zhang, RY., Du, WQ., Zhang, YC. et al. PLCε signaling in cancer. J Cancer Res Clin Oncol 142, 715–722 (2016). https://doi.org/10.1007/s00432-015-1999-x
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DOI: https://doi.org/10.1007/s00432-015-1999-x