腎上腺素能受體影響腫瘤發(fā)生發(fā)展的研究進(jìn)展

，

(1.天津中醫(yī)藥大學(xué)，天津 300193；2.天津中醫(yī)藥大學(xué)第一附屬醫(yī)院，天津 300193)

腎上腺素能受體影響腫瘤發(fā)生發(fā)展的研究進(jìn)展

管素芬1，夏天2*

(1.天津中醫(yī)藥大學(xué)，天津 300193；2.天津中醫(yī)藥大學(xué)第一附屬醫(yī)院，天津 300193)

研究認(rèn)為，腎上腺素能受體在某些外在因素或者藥物的作用下被各種腫瘤所激活，并通過一定的信號(hào)轉(zhuǎn)導(dǎo)通路引發(fā)一系列的效應(yīng)，進(jìn)而調(diào)節(jié)腫瘤的發(fā)生與發(fā)展。研究腎上腺素能受體信號(hào)調(diào)節(jié)腫瘤細(xì)胞的過程，可以更全面掌握腫瘤的形成及發(fā)展機(jī)制，從而為腫瘤的預(yù)防和治療開辟新的途徑。

腎上腺素能受體;α-AR;β-AR;腫瘤;信號(hào)轉(zhuǎn)導(dǎo);細(xì)胞周期

近年來(lái)，兒茶酚胺類激素及其受體對(duì)腫瘤發(fā)生、發(fā)展的影響是研究的一個(gè)熱點(diǎn)[1]。腎上腺素能受體(AR)是一種G蛋白偶聯(lián)受體，其作用方式多樣,被活化后可以通過不同的信號(hào)轉(zhuǎn)導(dǎo)方式對(duì)腫瘤細(xì)胞造成影響。本文就腎上腺素能受體對(duì)腫瘤的影響作一綜述。

1 腎上腺素能受體的亞型

腎上腺素能受體有2種分型，分別為α受體和β受體，而這2種受體又細(xì)分為若干受體亞型[2]。其亞型包括3個(gè)α1亞型(α1a,α1b,α1c),3個(gè)α2亞型(α2A,α2B,α2C)和3個(gè)β亞型(β1,β2,β3)。三個(gè)α1亞型的受體與藥理學(xué)分類的α1受體亞型有一定差異[3]。

2 腎上腺素能受體信號(hào)轉(zhuǎn)導(dǎo)通路

已經(jīng)發(fā)現(xiàn)腎上腺素能受體的信號(hào)轉(zhuǎn)導(dǎo)通路能調(diào)節(jié)多種腫瘤細(xì)胞過程，包括細(xì)胞增殖，細(xì)胞凋亡，細(xì)胞趨化、轉(zhuǎn)移及侵襲等[4]。

2.1 α腎上腺素能受體 α腎上腺素能受體(α-AR)主要通過激酶系統(tǒng)、耦聯(lián)離子通道等調(diào)控腫瘤的發(fā)生與發(fā)展。研究發(fā)現(xiàn)慢性心理應(yīng)激引起的腎上腺素分泌增多可激活α2-AR-MAPK(絲裂原活化蛋白激酶)通路上調(diào)ABCB1基因的表達(dá)，從而引起結(jié)腸癌細(xì)胞的多藥耐藥反應(yīng)，使得化療的難度增加[5]。洛杉磯加州大學(xué)醫(yī)學(xué)院[6]對(duì)乳腺癌細(xì)胞的研究中發(fā)現(xiàn)，α1-AR抑制劑多沙唑嗪可以阻斷EGFR(生長(zhǎng)因子受體)和NF-KappaB(核轉(zhuǎn)錄因子)的信號(hào)轉(zhuǎn)導(dǎo)通路，同時(shí)降低ERK1/2(細(xì)胞外信號(hào)調(diào)節(jié)激酶1/2)水平，從而達(dá)到抑制腫瘤細(xì)胞增殖并誘導(dǎo)其凋亡的效用。

Thebault S等[7]通過對(duì)人類前列腺癌上皮細(xì)胞和前列腺癌細(xì)胞這2種細(xì)胞株研究發(fā)現(xiàn)，激活α1-AR后，其可以通過二酰甘油(DAG)門控耦合質(zhì)膜上的陽(yáng)離子通道形成陽(yáng)離子膜電流，引發(fā)鈣離子的涌入，從而促進(jìn)前列腺癌細(xì)胞的增殖。在對(duì)倉(cāng)鼠成纖維細(xì)胞的研究[8]中發(fā)現(xiàn),在鈉氫轉(zhuǎn)換器(NHE1)的作用下α1-AR能夠提高M(jìn)MP-9(基質(zhì)金屬蛋白酶9)的表達(dá)水平，從而可以促進(jìn)癌細(xì)胞的侵襲與轉(zhuǎn)移。

2.2 β腎上腺素能受體 β腎上腺素能受體(β-AR)主要通過cAMP-PKA信號(hào)轉(zhuǎn)導(dǎo)途徑影響腫瘤的發(fā)生發(fā)展。研究表明，多種腫瘤細(xì)胞中的β腎上腺素能受體(β-AR)活化后產(chǎn)生第二信使cAMP(環(huán)磷酸腺苷)，繼而通過激活cAMP依賴的PKA(蛋白激酶A)通路調(diào)控腫瘤的發(fā)展[9]。在肝癌的細(xì)胞實(shí)驗(yàn)中，Kassahun等[10]發(fā)現(xiàn)激活腫瘤細(xì)胞內(nèi)β-AR后可增加AC(腺苷酸環(huán)化酶)的應(yīng)答性。經(jīng)過cAMP通路后活化β2-AR可降低VLA-4(一種整合素)的親和力，促使腫瘤細(xì)胞侵襲血管[11]。另有研究[12]發(fā)現(xiàn),β-AR通過cAMP-PKA信號(hào)轉(zhuǎn)導(dǎo)通路可增強(qiáng)腫瘤的血管形成，上調(diào)MMP-2和MMP-9(基質(zhì)金屬蛋白酶2、9)、VEGF(血管內(nèi)皮生長(zhǎng)因子)等分子的表達(dá)水平，從而促進(jìn)腫瘤的生成。美國(guó)田納西大學(xué)在吸煙與非小細(xì)胞肺癌的關(guān)系研究[13]中發(fā)現(xiàn),煙堿型乙酰膽堿受體(nAChRs)與p-CREB和p-ERK1/2神經(jīng)遞質(zhì)可以刺激NE(去甲腎上腺素)的合成,而NE可以在cAMP通路下導(dǎo)致促瘤效應(yīng)。

除了上述的cAMP通路外，β-AR亦可通過激酶系統(tǒng)影響腫瘤的發(fā)生發(fā)展。Kimura等[14]在研究卵巢癌的過程中發(fā)現(xiàn)促性腺激素釋放激素激動(dòng)劑(GnRHa)的一個(gè)下游分子(β-AR)可通過絲裂原活化蛋白激酶——Erk激酶通路影響卵巢癌的發(fā)展。另有研究[15]表明，NNK(煙草致癌原)活化β1-AR/β2-AR后可進(jìn)一步磷酸化Erk1/2激酶，從而導(dǎo)致胰腺癌的發(fā)生。在胰腺癌的研究中，Huang XY等[16]發(fā)現(xiàn)β-AR激動(dòng)劑NE能促進(jìn)P38/MAPK磷酸化，增加PANC-1細(xì)胞的S期數(shù)量，同時(shí)減少G1和G2期數(shù)量，并能顯著增強(qiáng)PANC-1細(xì)胞增殖、遷移和侵襲。而Schuller等[17]在對(duì)人類小細(xì)胞肺癌的研究之中亦得到了相似的結(jié)論：在胰腺癌的研究中首次表明肺癌中β-AR-PKA/CREB介導(dǎo)的信號(hào)通路也發(fā)揮了作用。另外，Dhar MS等[18]在乳腺癌研究中發(fā)現(xiàn)β-AR能與G蛋白內(nèi)向整流鉀通道(GIRK)偶聯(lián)，以此促進(jìn)乳腺癌細(xì)胞的生長(zhǎng)。

除以上機(jī)制外，亦有β-AR的其他信號(hào)轉(zhuǎn)導(dǎo)途徑。如法國(guó)里爾大學(xué)[19]通過乳腺癌細(xì)胞實(shí)驗(yàn)證明了HIC1是β2-AR的直接靶基因，通過激動(dòng)劑刺激β2-AR增加了高度惡性的MDA-MB-231乳腺癌細(xì)胞。同時(shí)Campbell等[20]對(duì)乳腺癌骨轉(zhuǎn)移的細(xì)胞實(shí)驗(yàn)發(fā)現(xiàn)，骨髓成骨細(xì)胞中RANKL(核因子KB受體活化因子配體)表達(dá)在β-AR活化后通過獨(dú)立的SDF1-CXCR4信號(hào)增加了體外的轉(zhuǎn)移性MDA-231細(xì)胞的遷移。

3 腎上腺素能受體與腫瘤細(xì)胞周期

眾所周知，由于腫瘤細(xì)胞周期的調(diào)節(jié)失控可以影響腫瘤的發(fā)生與發(fā)展。在對(duì)胃癌的一項(xiàng)研究[21]中發(fā)現(xiàn),尼古丁活化β-AR后可激活COX-2(環(huán)氧合酶-2)從而進(jìn)一步影響細(xì)胞周期蛋白,促使細(xì)胞周期中G1期向S期的過渡，從而增加癌細(xì)胞的生長(zhǎng)。而復(fù)旦大學(xué)兒童醫(yī)院研究[22]發(fā)現(xiàn)，β-AR拮抗劑能抑制嬰幼兒血管瘤細(xì)胞G0/G1期,降低相關(guān)蛋白D1、CDK-4、CDK-6的表達(dá)從而抑制細(xì)胞的增殖。除此之外，Liao X等[23]亦對(duì)2種胃腺癌細(xì)胞株(SGC-7901 and BGC-823)進(jìn)行研究，發(fā)現(xiàn)β-AR拮抗劑普萘洛爾通過下游NF-κB-VEGF/MMP-2/9/COX-2通路抑制細(xì)胞G0/G1期與G2/M期，從而抑制細(xì)胞增殖，并用Annexin V染色法測(cè)定其誘導(dǎo)細(xì)胞凋亡的細(xì)胞株。

Ishizuka T等[24]通過培養(yǎng)白血病抑制因子誘導(dǎo)的多功能小鼠干細(xì)胞發(fā)現(xiàn)，刺激α1-AR能促進(jìn)細(xì)胞S期與G2/M期，同時(shí)抑制G1期，進(jìn)而增強(qiáng)小鼠干細(xì)胞DNA的合成，促進(jìn)干細(xì)胞增殖，達(dá)到治療白血病的目的。在胰腺癌研究[25]中發(fā)現(xiàn)，β-AR拮抗劑可以阻斷NF-κB、細(xì)胞外信號(hào)調(diào)節(jié)激酶和Akt途徑，通過誘導(dǎo)上游分子RAS使胰腺癌細(xì)胞停滯于G1/S期,從而達(dá)到抑制細(xì)胞增殖與侵襲以及刺激細(xì)胞凋亡的作用。

4 腎上腺素能受體的其他作用

腎上腺素能受體對(duì)相關(guān)基因的調(diào)控與腫瘤的發(fā)生發(fā)展有一定的關(guān)系。Perez-Sayans M利用DNA微陣列的基因的差異表達(dá)發(fā)現(xiàn)，在口腔鱗狀細(xì)胞癌中β2-AR活化后可以導(dǎo)致ADRBK2基因的表達(dá)上調(diào)[26]。Park J K等[27]發(fā)現(xiàn)β2-AR激動(dòng)劑能增加胰腺癌細(xì)胞中miR-132與miR-212表達(dá)。此外，Sayed D等[28]研究發(fā)現(xiàn),β-AR可以刺激microRNA-21上調(diào)與SPRY2(一種磷蛋白)下調(diào)的表達(dá)水平,從而使結(jié)腸癌癌細(xì)胞突起生成增多，利于其侵襲與擴(kuò)散。

5 小結(jié)

除了大量資料表明腎上腺素能受體具有促瘤效應(yīng)之外，也有研究發(fā)現(xiàn)腎上腺素能受體具備抑瘤作用，其對(duì)抑癌基因和調(diào)節(jié)細(xì)胞凋亡的相關(guān)分子也有影響[29]。大量資料證實(shí)腎上腺素能受體對(duì)腫瘤的發(fā)生與發(fā)展起著重要的作用，通過研究腎上腺素能受體信號(hào)調(diào)節(jié)腫瘤細(xì)胞的過程，可以更全面掌握腫瘤的形成及發(fā)展機(jī)制，為腫瘤的預(yù)防和治療開辟新的途徑。

[1]Perrone M G,Notarnicola M,Caruso M G,et al.Upregulation of beta3-adrenergic receptor mRNA in human colon cancer:a preliminary study[J].Oncology,2008,75(3/4):224-229.

[2]鄭恒,錢家慶.腎上腺素受體信號(hào)轉(zhuǎn)導(dǎo)通路對(duì)心功能的調(diào)節(jié)及機(jī)制[J].國(guó)外醫(yī)學(xué)(生理、病理科學(xué)與臨床分冊(cè)),2000(4):303-305.

[3] Bylund D B.Subtypes of α1-and α2-adrenergic receptors[J].The FASEB journal,1992,6(3):832-839.

[4]Cole S W,Sood A K.Molecular pathways:beta-adrenergic signaling in cancer[J].Clin Cancer Res,2012,18(5):1201-1206.

[5]Yao H,Duan Z,Wang M,et al.Adrenaline induces chemoresistance in HT-29 colon adenocarcinoma cells[J].Cancer Genet Cytogenet,2009,190(2):81-87.

[6]Hui H X,Fernando M A,Heaney A P.The alpha(1)-adrenergic receptor antagonist doxazosin inhibits EGFR and NF-kappa B signalling to induce breast cancer cell apoptosis[J].Eur J Cancer,2008,44(1):160-166.

[7]Thebault S,Roudbaraki M,Sydorenko V,et al.Alpha1-adrenergic receptors activate Ca(2+)-permeable cationic channels in prostate cancer epithelial cells[J].J Clin Invest,2003,111(11):1691-1701.

[8]Taves J,Rastedt D,Canine J,et al.Sodium Hydrogen exchanger and phospholipase D are required for alpha1-adrenergic receptor stimulation of metalloproteinase-9 and cellular invasion in CCL39 fibroblasts[J].Arch Biochem Biophys,2008,477(1):60-66.

[9]Akhter S A,Milano C A,Shotwell K F,et al.Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors.In vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling[J].J Biol Chem,1997,272(34):21253-21259.

[10]Kassahun W T,Guenl B,Ungemach F R,et al.Expression and functional coupling of liver beta(2)-Adrenoceptors in the human hepatocellular carcinoma[J].Pharmacology,2012,89(5/6):313-320.

[11]Chigaev A,Waller A,Amit O,et al.Galphas-coupled receptor signaling actively down-regulates α4β1-integrin affinity:A possible mechanism for cell de-adhesion[J].BMC Immunol,2008,9(1):26.

[12]Thaker P H,Lutgendorf S K,Sood A K.The neuroendocrine impact of chronic stress on cancer[J].Cell Cycle,2007,6(4):430-433.

[13]Al-Wadei H A N,Al-Wadei M H,Schuller H M.Cooperative regulation of non-small cell lung carcinoma by nicotinic and beta-adrenergic receptors:a novel target for intervention[J].PLoS One,2012,7(1):e29915.

[14]Kimura A,Ohmichi M,Kurachi H,et al.Role of mitogen-activated protein kinase/extracellular signal-regulated kinase cascade in gonadotropin-releasing hormone-induced growth inhibition of a human ovarian cancer cell line[J].Cancer Res,1999,59(20):5133-5142.

[15]Askari M D,Tsao M S,Schuller H M.The tobacco-specific carcinogen,4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone stimulates proliferation of immortalized human pancreatic duct epithelia through beta-adrenergic transactivation of EGF receptors[J].J Cancer Res Clin Oncol,2005,131(10):639-648.

[16]Huang X Y,Wang H C,Yuan Z,et al.Norepinephrine stimulates pancreatic cancer cell proliferation,migration and invasion via beta-Adrenergic Receptor-Dependent activation of P38/MAPK pathway[J].Hepatogastroenterology,2012,59(115):889-893.

[17]Schuller H M.Nitrosamines as nicotinic receptor ligands[J].Life Sci,2007,80(24/25):2274-2280.

[18]Dhar M S,Plummer H K.Protein expression of G-protein inwardly rectifying potassium channels (GIRK) in breast cancer cells[J].BMC physiology,2006,6(1):8.

[19]Boulay G,Malaquin N,Loison I,et al.Loss of hypermethylated in cancer 1 (HIC1) in breast cancer cells contributes to stress-induced migration and invasion through β-2 adrenergic receptor (ADRB2) misregulation[J].J Biol Chem,2012,287(8):5379-5389.

[20]Campbell J P,Karolak M R,Ma Y,et al.Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice[J].PLoS biology,2012,10(7):e1001363.

[21]Shin V Y,Jin H C,Ng E K,et al.Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induce cyclooxygenase-2 activity in human gastric cancer cells:Involvement of nicotinic acetylcholine receptor (nAChR) and beta-adrenergic receptor signaling pathways[J].Toxicol Appl Pharmacol,2008,233(2):254-261.

[22]Ji Y,Chen S,Li K,et al.The role of beta-adrenergic receptor signaling in the proliferation of hemangioma-derived endothelial cells[J].Cell Div,2013,8(1):1.

[23]Liao X,Che X,Zhao W,et al.The β-adrenoceptor antagonist,propranolol,induces human gastric cancer cell apoptosis and cell cycle arrest via inhibiting nuclear factor κB signaling[J].Oncol Rep,2010,24(6):1669-1676.

[24]Ishizuka T,Watanabe Y.α-Adrenoceptor stimulation enhances leukemia inhibitory factor-induced proliferation of mouse-induced pluripotent stem cells[J].Eur J Pharmacol,2011,668(1/2):42-56.

[25]Zhang D,Ma Q,Wang Z,et al.β2-adrenoceptor blockage induces G1/S phase arrest and apoptosis in pancreatic cancer cells via Ras/Akt/NFκB pathway[J].Mol Cancer,2011,10:146.

[26]Pérez-Sayáns M,Somoza-Martín J M,Barros-Angueira F,et al.Activity of β2-adrenergic receptor in oral squamous cell carcinoma is mediated by overexpression of the ADRBK2 gene:a pilot study[J].Biotechnic & Histochemistry,2012,87(3):179-186.

[27]Park J K,Henry J C,Jiang J,et al.miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor[J].Biochem Biophys Res Commun,2011,406(4):518-523.

[28]Sayed D,Rane S,Lypowy J,et al.MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths[J].Mol Biol Cell,2008,19(8):3272-3282.

[29]Thompson T C.Suppression of tumor suppressors in prostate cancer:The emergence of a novel oncogenic pathway[J].Cancer Cell,2007,12(5):405-407.

Effectontheoccurrenceanddevelopmentoftumorbyadrenergicreceptor:areview

GUAN Sufen1,XIA Tian2*

(1.Tianjin University of Traditional Chinese Medicine,Tianjin 300193,China;2.First Hospital Affiliated to Tianjin University of Traditional Chinese Medicine,Tianjin 300193,China)

In recent years,many studies suggest that adrenergic receptor is activated by various tumors in some external factors or the drug,and regulate the occurrence and development of tumor by certain signal transduction pathways triggering a series of effects,which is helpful to further understand the mechanism of the occurrence and development of tumor,thus providing a new direction for the prevention and treatment of tumor.

adrenergic receptor;α-AR;β-AR;tumor;signal transduction;;cell cycle

10.13463/j.cnki.cczyy.2014.05.076

國(guó)家自然科學(xué)基金“基于腎上腺素能受體信號(hào)轉(zhuǎn)導(dǎo)途徑研究肝郁—心理應(yīng)激對(duì)子宮肌瘤ER、PR的影響”(81072838)。

管素芬(1987-)，女，博士研究生。研究方向：中醫(yī)婦科學(xué)。

] 夏 天，主任醫(yī)師，電子信箱:xiatian76@163.com。

R273

：A

：2095-6258(2014)05-0959-04

2014-06-03)

*[