The objective of the present study was to repurpose L-menthol, which is frequently used in oral health and topical formulations, for cancer therapeutics. In this article, we argue that monoterpenes such as L-menthol might offer veritable potentials in systems medicine, for example, as cheaper anti-cancer compounds. Other monoterpenes such as limonene, perillyl alcohol, and geraniol have been shown to induce apoptosis in various cancer cell lines, but their mechanisms of action are yet to be completely elucidated. Earlier, we showed that L-menthol modulates tubulin polymerization and apoptosis to inhibit cancer cell proliferation. In the present report, we used an apoptosis-related gene microarray in conjunction with proteomics analyses, as well as in silico interpretations, to study gene expression modulation in human adenocarcinoma Caco-2 cell line in response to L-menthol treatment. The microarray analysis identified caspase 10 as the important initiator caspase, instead of caspase 8. The proteomics analyses showed downregulation of HSP90 protein (also corroborated by its low transcript abundance), which in turn indicated inhibition of AKT-mediated survival pathway, release of pro-apoptotic factor BAD from BAD and BCLxL complex, besides regulation of other factors related to apoptosis. Based on the combined microarray, proteomics, and in silico data, a signaling pathway for L-menthol-induced apoptosis is being presented for the first time here. These data and literature analysis have significant implications for “repurposing” L-menthol beyond oral medicine, and in understanding the mode of action of plant-derived monoterpenes towards development of cheaper anticancer drugs in future.
Get full access to this article
View all access options for this article.
References
1.
AdachiM, and ImaiK. (2002). The proapoptotic BH3-only protein BAD transduces cell death signals independently of its interaction with Bcl-2. Cell Death Differ, 9, 1240–1247.
2.
Al-ZoubiAM, EfimovaEV, KaithamanaS, et al. (2001). Contrasting effects of IG20 and its splice isoforms, MADD and DENN-SV, on tumor necrosis factor alpha-induced apoptosis and activation of caspase-8 and −3. J Biol Chem, 276, 47202–47211.
3.
AndohT, LeeSY, and ChiuehCC. (2000). Preconditioning regulation of bcl-2 and p66shc by human NOS1 enhances tolerance to oxidative stress. FASEB J, 14, 2144–2146.
4.
AryaR, MallikM, and LakhotiaSC. (2007). Heat shock genes—Integrating cell survival and death. J Biosci, 32, 595–610.
5.
BaileyHH, AttiaS, LoveRR, et al. (2008). Phase II trial of daily oral perillyl alcohol (NSC 641066) in treatment-refractory metastatic breast cancer. Cancer Chemother Pharmacol, 62, 149–157.
6.
BarthelmanM, ChenW, GenslerHL, HuangC, DongZ, and BowdenGT. (1998). Inhibitory effects of perillyl alcohol on UV-B-induced murine skin cancer and AP-1 transactivation. Cancer Res, 58, 711–716.
7.
BassoAD, SolitDB, ChiosisG, GiriB, TsichlisP, and RosenN. (2002). Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J Biol Chem, 277, 39858–39866.
8.
BelangerJT. (1998). Perillyl alcohol: Applications in oncology. Altern Med Rev, 3, 448–457.
9.
Brocke-HeidrichK, GeB, CvijicH, et al. (2006). Bcl-3 is induced by IL-6 via Stat3 binding to intronic enhancer HS4 and represses its own transcription. Oncogene, 25, 7297–7304.
10.
BurnetteWN. (1981). “Western blotting”: Electrophoretic transfer of proteins from sodium dodecyl sulfate–polyacrylamide gels to unmodified nitrocellulose and radiographic detection with antibody and radioiodinated protein A. Anal Biochem, 112, 195–203.
11.
BurtonTR, HensonES, AzadMB, BrownM, EisenstatDD, and GibsonSB. (2013). BNIP3 acts as transcriptional repressor of death receptor-5 expression and prevents TRAIL-induced cell death in gliomas. Cell Death Dis, 4, e587.
12.
CastellanoR, VireB, PionM, et al. (2006). Active transcription of the human FASL/CD95L/TNFSF6 promoter region in T lymphocytes involves chromatin remodeling: Role of DNA methylation and protein acetylation suggest distinct mechanisms of transcriptional repression. J Biol Chem, 281, 14719–14728.
13.
ChenG, CaoP, and GoeddelDV. (2002). TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. Mol Cell, 9, 401–410.
14.
ChenG, RongM, and LuoD. (2010). TNFRSF6B neutralization antibody inhibits proliferation and induces apoptosis in hepatocellular carcinoma cell. Pathol Res Pract, 206, 631–641.
ChenTC, FonsecaCO, and SchönthalAH. (2015). Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy. Am J Cancer Res, 5, 1580–1593.
17.
ChicasA, KapoorA, WangX, et al. (2012). H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence. Proc Natl Acad Sci USA, 109, 8971–8976.
18.
ChinnaduraiG, VijayalingamS, and RashmiR. (2008). BIK, the founding member of the BH3-only family proteins: Mechanisms of cell death and role in cancer and pathogenic processes. Oncogene, 27, S20–S29.
ClarkSS, ZhongL, FiliaultD, et al. (2003). Anti-leukemia effect of perillyl alcohol in Bcr/Abl-transformed cells indirectly inhibits signaling through Mek in a Ras- and Raf-independent fashion. Clin Cancer Res, 9, 4494–4504.
21.
DandaraC, HuzairF, Borda-RodriguezA, et al. (2014). H3Africa and the African life sciences ecosystem: Building sustainable innovation. OMICS, 18, 733–739.
22.
da FonsecaCO, SchwartsmannG, FischerJ, et al. (2008). Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas. Surg Neurol, 70, 259–266.
23.
DiasS, ShmelkovSV, LamG, and RafiiS. (2002). VEGF (165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. Blood, 99, 2532–2540.
24.
DickFA. (2007). Structure-function analysis of the retinoblastoma tumor suppressor protein—Is the whole a sum of its parts?. Cell Div, 2, 26.
25.
EbmeyerJ, LeichtleA, HernandezM, et al. (2011). TNFA deletion alters apoptosis as well as caspase 3 and 4 expression during otitis media. BMC Immunol, 12, 12.
26.
FaridiU, SisodiaBS, ShuklaAK, et al. (2011). Proteomics indicates modulation of tubulin polymerization by L-menthol inhibiting human epithelial colorectal adenocarcinoma cell proliferation. Proteomics, 11, 2115–2119.
27.
Fernandes-AlnemriT, ArmstrongRC, KrebsJ, et al. (1996). In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proc Natl Acad Sci USA, 93, 7464–7469.
28.
FrommerKW, ReichenmillerK, SchuttBS, et al. (2006). IGF-independent effects of IGFBP-2 on the human breast cancer cell line Hs578T. J Mol Endocrinol, 37, 13–23.
29.
FumotoS, TanimotoK, HiyamaE, NoguchiT, NishiyamaM, and HiyamaK. (2009). EMP3 as a candidate tumor suppressor gene for solid tumors. Expert Opin Ther Targets, 13, 811–822.
30.
GhoshJC, DohiT, KangBH, and AltieriDC. (2008). Hsp60 regulation of tumor cell apoptosis. J Biol Chem, 283, 5188–5194.
31.
GongF, YangL, TaiF, HuX, and WangW. (2014). “Omics” of maize stress response for sustainable food production: Opportunities and challenges. OMICS, 18, 714–732.
32.
GuoB, GodzikA, and ReedJC. (2001). Bcl-G, a novel pro-apoptotic member of the Bcl-2 family. J Biol Chem, 276, 2780–2785.
33.
HaagJD, LindstromMJ, and GouldMN. (1992). Limonene-induced regression of mammary carcinomas. Cancer Res, 52, 4021–4026.
34.
HillE, ClarkeM, and BarrFA. (2000). The Rab6-binding kinesin, Rab6-KIFL, is required for cytokinesis. EMBO J, 19, 5711–5719.
35.
HengartnerMO. (2000). The biochemistry of apoptosis. Nature, 407, 770–776.
36.
HerrmannM, LorenzHM, VollR, GrünkeM, WoithW, and KaldenJR. (1994). A rapid and simple method for the isolation of apoptotic DNA fragments. Nucleic Acids Res, 22, 5506–5507.
37.
HitomiJ, KatayamaT, EguchiY, et al. (2004). Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death. J Cell Biol, 165, 347–356.
38.
HsiaKT, MillarMR, KingS, et al. (2003). DNA repair gene Ercc1 is essential for normal spermatogenesis and oogenesis and for functional integrity of germ cell DNA in the mouse. Development, 130, 369–378.
39.
HsuYT, WolterKG, and YouleRJ. (1997). Cytosol-to-membrane redistribution of Bax and Bcl-x(L) during apoptosis. Proc Natl Acad Sci USA, 94, 3668–3672.
40.
HuS, VincenzC, NiJ, GentzR, and DixitVM. (1997). I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1-and CD-95-induced apoptosis. J Biol Chem, 272, 17255–17257.
41.
HuangC, MaWY, GoransonA, and DongZ. (1999). Resveratrol suppresses cell transformation and induces apoptosis through a p53-dependent pathway. Carcinogenesis, 20, 237–242.
42.
InoharaN, GourleyTS, CarrioR, et al. (1998). Diva, a Bcl-2 homologue that binds directly to Apaf-1 and induces BH3-independent cell death. J Biol Chem, 273, 32479–32486.
43.
JakobiR, MoertlE, and KoeppelMA. (2001). p21-activated protein kinase gamma-PAK suppresses programmed cell death of BALB3T3 fibroblasts. J Biol Chem, 276, 16624–16634.
44.
JiaSS, XiGP, ZhangM, et al. (2013). Induction of apoptosis by D-limonene is mediated by inactivation of Akt in LS174T human colon cancer cells. Oncol Rep, 29, 349–354.
45.
JustenhovenC, HamannU, PeschB, et al. (2004). ERCC2 genotypes and a corresponding haplotype are linked with breast cancer risk in a German population. Cancer Epidemiol Biomarkers Prev, 13, 2059–2064.
46.
KaleVP, AminSG, and PandeyMK. (2015) Targeting ion channels for cancer therapy by repurposing the approved drugs. Biochim Biophys Acta, 1848, 2747–2755.
47.
KatoS, MoulderSL, UenoNT, et al. (2015) Challenges and perspective of drug repurposing strategies in early phase clinical trials. Oncoscience, 2, 576–580.
48.
KashiiY, GiordaR, HerbermanRB, WhitesideTL, and VujanovicNL. (1999). Constitutive expression and role of the TNF family ligands in apoptotic killing of tumor cells by human NK cells. J Immunol, 163, 5358–5366.
49.
KawaiT, MatsumotoM, TakedaK, SanjoH, and AkiraS. (1998). ZIP kinase, a novel serine/threonine kinase which mediates apoptosis. Mol Cell Biol, 18, 1642–1651.
50.
KimST, LimDS, CanmanCE, and KastanMB. (1999). Substrate specificities and identification of putative substrates of ATM kinase family members. J Biol Chem, 274, 37538–37543.
51.
KimWY, and ShenJ. (2008). Presenilins are required for maintenance of neural stem cells in the developing brain. Mol Neurodegener, 3, 2.
52.
KischkelFC, LawrenceDA, TinelA, et al. (2001). Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8. J Biol Chem, 276, 46639–46646.
53.
KleinJA, Longo-GuessCM, RossmannMP, et al. (2002). The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature, 419, 367–374.
54.
KooijmanR. (2006). Regulation of apoptosis by insulin-like growth factor (IGF)-I. Cytokine Growth Factor Rev, 17, 305–323.
55.
KotturiMF, CarlowDA, LeeJC, ZiltenerHJ, and JefferiesWA. (2003). Identification and functional characterization of voltage-dependent calcium channels in T lymphocytes. J Biol Chem, 278, 46949–46960.
56.
KraskouskayaD, DuoduE, ArpinCC, and GunningPT. (2013). Progress towards the development of SH2 domain inhibitors. Chem Soc Rev, 42, 3337–3370.
57.
LewisJ, DevinA, MillerA, et al. (2000). Disruption of hsp90 function results in degradation of the death domain kinase, receptor interacting protein (RIP), and blockage of tumor necrosis factor-induced nuclear factor-kappaB activation. J Biol Chem, 275, 10519–10526.
58.
LiT, DaiW, and LuL. (2002). Ultraviolet-induced junD activation and apoptosis in myeloblastic leukemia ML-1 cells. J Biol Chem, 277, 32668–32676.
59.
LiP, NijhawanD, BudihardjoI, et al. (1997). Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell, 91, 479–489.
60.
LiaoG, ZhangM, HarhajEW, and SunSC. (2004). Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J Biol Chem, 279, 26243–26250.
61.
LiptonSA, and Bossy-WetzelE. (2002). Dueling activities of AIF in cell death versus survival: DNA binding and redox activity. Cell, 111, 147–150.
62.
Loza-TaveraH. (1999). Monoterpenes in essential oils: Biosynthesis and properties. Adv Exp Med Biol, 464, 49–62.
63.
LuoN, WuY, ChenY, et al. (2009). Upregulated BclG(L) expression enhances apoptosis of peripheral blood CD4+ T lymphocytes in patients with systemic lupus erythematosus. Clin Immunol, 132, 349–361.
64.
MaaserK, GrabowskiP, SutterAP, et al. (2002). Overexpression of the peripheral benzodiazepine receptor is a relevant prognostic factor in stage III colorectal cancer. Clin Cancer Res, 8, 3205–3209.
65.
MatsumuraY, MatsumuraY, NishigoriC, HorioT, and MiyachiY. (2004). PIG7/LITAF gene mutation and overexpression of its gene product in extramammary Paget's disease. Int J Cancer, 111, 218–223.
66.
McCabeB, LiberanteF, and MillsKI. (2015) Repurposing medicinal compounds for blood cancer treatment. Ann Hematol, 94, 1267–1276.
67.
McPhillipsF, MullenP, MacLeodKG, et al. (2006). Raf-1 is the predominant Raf isoform that mediates growth factor-stimulated growth in ovarian cancer cells. Carcinogenesis, 27, 729–739.
68.
MiH, MuruganujanA, CasagrandeJT, and ThomasPD. (2013). Large-scale gene function analysis with the PANTHER classification system. Nat Protoc, 8, 1551–1566.
69.
MilhasD, CuvillierO, ThervilleN, et al. (2005). Caspase-10 triggers bid cleavage and caspase cascade activation in FasL-induced apoptosis. J Biol Chem, 280, 19836–19842.
70.
MillerJA, PappanK, ThompsonPA, et al. (2015). Plasma metabolomic profiles of breast cancer patients after short-term limonene intervention. Cancer Prev Res (Phila), 8, 86–93.
71.
MillsJJ, ChariRS, BoyerIJ, GouldMN, and JirtleRL. (1995). Induction of apoptosis in liver tumors by the monoterpene perillyl alcohol. Cancer Res, 55, 979–983.
72.
MounayarR, MorzelM, BrignotH, et al. (2014) Nutri-metabolomics applied to taste perception phenotype: Human subjects with high and low sensitivity to taste of fat differ in salivary response to oleic acid. OMICS, 18, 666–672.
73.
NaderiA, TeschendorffAE, BeigelJ, et al. (2007). BEX2 is overexpressed in a subset of primary breast cancers and mediates nerve growth factor/nuclear factor-kappaB inhibition of apoptosis in breast cancer cell lines. Cancer Res, 67, 6725–6736.
74.
NagakawaH, ShimozatoO, YuL, et al. (2012). Expression of a murine homolog of apoptosis-inducing human IL-24/MDA-7 in murine tumors fails to induce apoptosis or produce anti-tumor effects. Cell Immunol, 275: 90–97.
75.
NapireiM, LudwigS, MezrhabJ, KlocklT, and MannherzHG. (2009). Murine serum nucleases—Contrasting effects of plasmin and heparin on the activities of DNase1 and DNase1-like 3 (DNase1l3). FEBS J, 276, 1059–1073.
76.
NapoliL, BordoniA, ZevianiM, et al. (2001). A novel missense adenine nucleotide translocator-1 gene mutation in a Greek adPEO family. Neurology, 57, 2295–2298.
77.
NielsenTO, AndrewsHN, CheangM, et al. (2004). Expression of the insulin-like growth factor I receptor and urokinase plasminogen activator in breast cancer is associated with poor survival: potential for intervention with 17-allylamino geldanamycin. Cancer Res, 64, 286–291.
78.
O'BrienNW, GellingsNM, GuoM, BarlowSB, GlembotskiCC, and SabbadiniRA. (2003). Factor associated with neutral sphingomyelinase activation and its role in cardiac cell death. Circ Res, 92, 589–591.
79.
OliverJL, AlexanderMP, NorrodAG, MullinsIM, and MullinsDW. (2013). Differential expression and tumor necrosis factor-mediated regulation of TNFRSF11b/osteoprotegerin production by human melanomas. Pigment Cell Melanoma Res, 26, 571–579.
80.
PandeyP, SalehA, NakazawaA, et al. (2000). Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J, 19, 4310–4322.
81.
PathanN, MarusawaH, KrajewskaM, et al., (2001). TUCAN, an antiapoptotic caspase-associated recruitment domain family protein overexpressed in cancer. J Biol Chem, 276, 32220–32229.
82.
PiñeiroD, MartínME, GuerraN, SalinasM, and GonzálezVM. (2007). Calpain inhibition stimulates caspase-dependent apoptosis induced by taxol in NIH3T3 cells. Exp Cell Res, 313, 369–379.
83.
PuthalakathH, VillungerA, O'ReillyLA, et al. (2001). Bmf: A proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science, 293, 1829–1832.
84.
ReddyBS, WangCX, SamahaH, et al. (1997). Chemoprevention of colon carcinogenesis by dietary perillyl alcohol. Cancer Res, 57, 420–425.
85.
RhoSB, ByunHJ, ParkSY, and ChunT. (2008). Calpain 6 supports tumorigenesis by inhibiting apoptosis and facilitating angiogenesis. Cancer Lett, 271, 306–313.
86.
RudelT, and BokochGM. (1997). Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2. Science, 276, 1571–1574.
87.
RudelT, ZenkeFT, ChuangTH, and BokochGM. (1998). p21-activated kinase (PAK) is required for Fas-induced JNK activation in Jurkat cells. J Immunol, 160, 7–11.
88.
SadkowskiT, JankM, ZwierzchowskiL, SiadkowskaE, OprzadekJ, and MotylT. (2008). Gene expression profiling in skeletal muscle of Holstein-Friesian bulls with single-nucleotide polymorphism in the myostatin gene 5′-flanking region. J Appl Genet, 49, 237–250.
89.
SahinMB, PermanSM, JenkinsG, and ClarkSS. (1999). Perillyl alcohol selectively induces G0/G1 arrest and apoptosis in Bcr/Abl-transformed myeloid cell lines. Leukemia, 13, 1581–1591.
90.
SahuJ, SenP, ChoudhuryMD, et al. (2014). Rediscovering medicinal plants' potential with OMICS: microsatellite survey in expressed sequence tags of eleven traditional plants with potent antidiabetic properties. OMICS, 18, 298–309.
91.
SitoleL, SteffensF, KrügerTP, and MeyerD. (2014). Mid-ATR-FTIR spectroscopic profiling of HIV/AIDS sera for novel systems diagnostics in global health. OMICS, 18, 513–523.
92.
SatoS, FujitaN, and TsuruoT. (2000). Modulation of Akt kinase activity by binding to Hsp90. Proc Natl Acad Sci USA, 97, 10832–10837.
93.
SchievellaAR, ChenJH, GrahamJR, and LinLL. (1997). MADD, a novel death domain protein that interacts with the type 1 tumor necrosis factor receptor and activates mitogen-activated protein kinase. J Biol Chem, 272, 12069–12075.
94.
SekoY, SugishitaK, SatoO, et al. (2004). Expression of costimulatory molecules (4-1BBL and Fas) and major histocompatibility class I chain-related A (MICA) in aortic tissue with Takayasu's arteritis. J Vasc Res, 41, 84–90.
95.
ShuHB, and JohnsonH. (2000). B cell maturation protein is a receptor for the tumor necrosis factor family member TALL-1. Proc Natl Acad Sci USA, 97, 9156–9161.
96.
SobralMV, XavierAL, LimaTC, and de SousaDP. (2014). Antitumor activity of monoterpenes found in essential oils. Sci World J, 2014, 953451.
97.
SoengasMS, CapodieciP, PolskyD, et al. (2001). Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature, 409, 207–211.
98.
SongY, and JacobCO. (2005). The mouse cell surface protein TOSO regulates Fas/Fas ligand-induced apoptosis through its binding to Fas-associated death domain. J Biol Chem, 280, 9618–9626.
99.
StarkMJ, BurkeYD, McKinzieJH, AyoubiAS, and CrowellPL. (1995). Chemotherapy of pancreatic cancer with the monoterpene perillyl alcohol. Cancer Lett, 96, 15–21.
100.
StayrookKR, McKinzieJH, BurkeYD, BurkeYA, and CrowellPL. (1997). Induction of the apoptosis-promoting protein Bak by perillyl alcohol in pancreatic ductal adenocarcinoma relative to untransformed ductal epithelial cells. Carcinogenesis, 18, 1655–1658.
101.
SturnA, QuackenbushJ, and TrajanoskiZ. (2002). Genesis: Cluster analysis of microarray data. Bioinformatics, 18, 207–208.
102.
SuXL, HouYL, YanXH, et al. (2012). Expression, purification, and evaluation for anticancer activity of ribosomal protein L31 gene (RPL31) from the giant panda (Ailuropoda melanoleuca). Mol Biol Rep, 39, 8945–8954.
103.
TadmouriA, KiyonakaS, BarbadoM, et al. (2012). Cacnb4 directly couples electrical activity to gene expression, a process defective in juvenile epilepsy. EMBO J, 31, 3730–3744.
104.
TaglialatelaG, RobinsonR, and Perez-PoloJR. (1997). Inhibition of nuclear factor kappa B (NFκB) activity induces nerve growth factor-resistant apoptosis in PC12 cells. J Neurosci Res, 47, 155–162.
105.
TakahashiK, NiidomeT, AkaikeA, KiharaT, and SugimotoH. (2009). Amyloid precursor protein promotes endoplasmic reticulum stress-induced cell death via C/EBP homologous protein-mediated pathway. J Neurochem, 109, 1324–1337.
106.
ValenciaCA, CottenSW, and LiuR. (2007). Cleavage of BNIP-2 and BNIP-XL by caspases. Biochem Biophys Res Commun, 364, 495–501.
107.
WangJ, ChunHJ, WongW, SpencerDM, and LenardoMJ. (2001). Caspase-10 is an initiator caspase in death receptor signaling. Proc Natl Acad Sci USA, 98, 13884–13888.
108.
WangL, DuF, and WangX. (2008). TNF-α induces two distinct caspase-8 activation pathways. Cell, 133, 693–703.
109.
WangY, RadhakrishnanD, HeX, PeehlDM, and EngC. (2013). Transcription factor KLLN inhibits tumor growth by AR suppression, induces apoptosis by TP53/TP73 stimulation in prostate carcinomas, and correlates with cellular differentiation. J Clin Endocrinol Metab, 98, E586–E594.
110.
WangY, RobertsonJD, and WalcheckB. (2011). Different signaling pathways stimulate a disintegrin and metalloprotease-17 (ADAM17) in neutrophils during apoptosis and activation. J Biol Chem, 286, 38980–38988.
WheelockMJ, and JohnsonKR. (2003). Cadherins as modulators of cellular phenotype. Annu Rev Cell Dev Biol, 19, 207–235.
113.
WisemanDA, WernerSR, and CrowellPL. (2007). Cell cycle arrest by the isoprenoids perillyl alcohol, geraniol, and farnesol is mediated by p21Cip1 and p27Kip1 in human pancreatic adenocarcinoma cells. J Pharmacol Exp Ther, 320, 1163–1170.
114.
WongBR, BesserD, KimN, et al. (1999). TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell, 4, 1041–1049.
115.
WongDCF, WongKTK, LeeYY, MorinPN, HengCK, and YapMGS. (2006). Transcriptional profiling of apoptotic pathways in batch and fed-batch CHO cell cultures. Biotechnol Bioeng, 94, 373–382.
116.
WuY, LiuXM, WangXJ, ZhangY, LiangXQ, and CaoEH. (2009). PIG11 is involved in hepatocellular carcinogenesis and its over-expression promotes Hepg2 cell apoptosis. Pathol Oncol Res, 15, 411–416.
117.
WylieAA, PulfordDJ, McVie-WylieAJ, et al. (2003). Tissue-specific inactivation of murine M6P/IGF2R. Am J Pathol, 162, 321–328.
118.
XiaoH, PalhanV, YangY, and RoederRG. (2000). TIP30 has an intrinsic kinase activity required for up-regulation of a subset of apoptotic genes. EMBO J, 19, 956–963.
119.
XuW, and NeckersL. (2007). Targeting the molecular chaperone heat shock protein 90 provides a multifaceted effect on diverse cell signaling pathways of cancer cells. Clin Cancer Res, 13, 1625–1629.
YouleRJ, and StrasserA. (2008). The BCL-2 protein family: Opposing activities that mediate cell death. Nat Rev Mol Cell Biol, 9, 47–59.
122.
YuSE, ParkSH, and JangYK. (2010). Epigenetic silencing of TNFSF7 (CD70) by DNA methylation during progression to breast cancer. Mol Cells, 29, 217–221.
123.
YuZ, WangW, XuL, DongJ, and JingY. (2008). d-Limonene and d-carvone induce apoptosis in HL-60 cells through activation of caspase-8. Asian J Trad Med, 3, 134–143.
124.
ZhangR, LuoD, MiaoR, et al. (2005). Hsp90-Akt phosphorylates ASK1 and inhibits ASK1-mediated apoptosis. Oncogene, 24, 3954–3963.
125.
ZhengY, YuB, AlexanderD, CouperDJ, and BoerwinkleE. (2014) Medium-term variability of the human serum metabolome in the Atherosclerosis Risk in Communities (ARIC) study. OMICS, 18, 364–373.
126.
ZhaoY, DingWX, QianT, WatkinsS, LemastersJJ, and YinXM. (2003). Bid activates multiple mitochondrial apoptotic mechanisms in primary hepatocytes after death receptor engagement. Gastroenterology, 125, 854–867.
127.
ZhaoC, and WangE. (2004). Heat shock protein 90 suppresses tumor necrosis factor alpha induced apoptosis by preventing the cleavage of Bid in NIH3T3 fibroblasts. Cell Signal, 16, 313–321.
128.
ZhuY, LiM, WangX, et al. (2012). Caspase cleavage of cytochrome c1 disrupts mitochondrial function and enhances cytochrome c release. Cell Res, 22, 127–141.
129.
ZongWX, LindstenT, RossAJ, MacGregorGR, and ThompsonCB. (2001). BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev, 15, 1481–1486.
130.
ZucchelliS, VilottiS, CalligarisR, et al. (2009). Aggresome-forming TTRAP mediates pro-apoptotic properties of Parkinson's disease-associated DJ-1 missense mutations. Cell Death Differ, 16, 428–438.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
