鐘 瑤,朱 琦上海交通大學(xué)附屬第九人民醫(yī)院血液內(nèi)科,上海 200011
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淋巴瘤和cAMP信號通路
鐘瑤,朱琦
上海交通大學(xué)附屬第九人民醫(yī)院血液內(nèi)科,上海 200011
[摘要]淋巴瘤細(xì)胞克隆性增殖和疾病進展涉及細(xì)胞內(nèi)多個信號通路。環(huán)腺苷酸(cyclic adenosine monophosphate,cAMP)信號通路作為一種重要的細(xì)胞內(nèi)信息傳遞系統(tǒng)參與細(xì)胞增殖、分泌、代謝和凋亡等多種生理過程的調(diào)控。靶向調(diào)變cAMP信號通路可以誘導(dǎo)多種惡性淋巴瘤細(xì)胞增殖阻滯和凋亡,其機制涉及線粒體介導(dǎo)細(xì)胞凋亡、cAMP調(diào)控蛋白激酶和多種細(xì)胞內(nèi)調(diào)控因子。對cAMP介導(dǎo)淋巴瘤細(xì)胞凋亡深入研究分析,將為臨床治療淋巴瘤提供可能途徑和潛在靶點。
[關(guān)鍵詞]淋巴瘤;環(huán)腺苷酸信號通路;細(xì)胞凋亡
淋巴瘤是起源于淋巴結(jié)和淋巴組織的淋巴細(xì)胞克隆增殖性疾病,其發(fā)生與免疫應(yīng)答過程中淋巴細(xì)胞異常增殖、分化和凋亡密切相關(guān)。作為最常見的血液腫瘤,淋巴瘤具有高度異質(zhì)性,其生物學(xué)特征、臨床進程及預(yù)后各不相同[1]。目前淋巴瘤臨床治療藥物包括糖皮質(zhì)激素和烷化劑等細(xì)胞毒藥物及基于特定分子靶標(biāo)的靶向藥物(如利妥昔單抗等),其中基于靶向藥物的聯(lián)合化療顯著提高部分淋巴瘤患者臨床緩解率和治愈率[2]。此外,一些新型治療手段(如造血干細(xì)胞移植和細(xì)胞免疫治療等)使部分復(fù)發(fā)或難治性淋巴瘤患者獲得緩解并延長其生存期[3-5]。但目前仍有相當(dāng)一部分淋巴瘤患者對現(xiàn)有治療方案不敏感或療效欠佳而成為“真正”難治性患者[4]。因此,深入探究淋巴瘤細(xì)胞異常生長的細(xì)胞和分子機制并發(fā)現(xiàn)潛在治療靶標(biāo)或途徑有其必要性和重要臨床意義[6]。近年來大量研究顯示,通過調(diào)變細(xì)胞內(nèi)環(huán)腺苷酸(cyclic adenosine monophosphate,cAMP)信號通路不僅可以誘導(dǎo)多種惡性淋巴細(xì)胞增殖阻滯和凋亡,而且能夠增強惡性淋巴細(xì)胞對糖皮質(zhì)激素等化療藥物的敏感性,cAMP信號通路成為淋巴瘤治療的潛在靶標(biāo)[7]?,F(xiàn)對cAMP信號通路在不同惡性淋巴瘤細(xì)胞凋亡中的作用及靶向調(diào)變該通路誘導(dǎo)淋巴瘤細(xì)胞凋亡可能機制和臨床應(yīng)用前景進行綜述。
cAMP作為一種普遍細(xì)胞內(nèi)第二信使通過其下游效應(yīng)分子調(diào)控細(xì)胞多種生理過程,這些效應(yīng)分子包括cAMP依賴蛋白激酶A(cyclic-AMPdependent protein kinase A,PKA)和cAMP活化轉(zhuǎn)換蛋白(exchange protein directly activated by cAMP,EPAC)等。cAMP信號通路調(diào)變的細(xì)胞生物學(xué)效應(yīng)取決于細(xì)胞類型和細(xì)胞內(nèi)特定環(huán)境[8]。有研究顯示,淋巴瘤細(xì)胞內(nèi)cAMP信號通路激活通常導(dǎo)致其增殖阻滯和凋亡,提高細(xì)胞內(nèi)cAMP水平能夠誘導(dǎo)多種淋巴瘤細(xì)胞凋亡[7, 9]。
彌漫大B細(xì)胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)是臨床最常見高度異質(zhì)性B細(xì)胞淋巴瘤。腺苷酸環(huán)化酶(adenylyl cyclase,AC)激動劑佛司可林(forskolin)通過提高DLBCL細(xì)胞內(nèi)cAMP水平而誘導(dǎo)其細(xì)胞增殖阻滯和凋亡。但部分難治性DLBCL細(xì)胞內(nèi)因高表達(dá)磷酸二酯酶(phosphodiesterase,PDE)4B使其細(xì)胞內(nèi)cAMP迅速降解而削弱forskolin介導(dǎo)細(xì)胞活力下降。Forskolin聯(lián)合PDE4B特異性抑制劑哈利普蘭(rolipram)或PLX513能夠使難治性DLBCL細(xì)胞內(nèi)cAMP水平升高進而誘導(dǎo)其細(xì)胞增殖和活力下降[10]。此外,DLBCL細(xì)胞內(nèi)PDE4B高表達(dá)可降低細(xì)胞內(nèi)cAMP水平而削弱cAMP對磷脂酰肌醇3激酶/蛋白激酶B/哺乳動物雷帕霉素靶蛋白(phosphatidylinositol-3-kinase/protein kinase B/the mammalian target of rapamycin,PI3K/AKT/mTOR)信號通路的抑制作用,導(dǎo)致DLBCL細(xì)胞內(nèi)AKT通路激活而使其對糖皮質(zhì)激素藥物(如地塞米松等)耐藥[11]。有研究顯示,提高DLBCL細(xì)胞內(nèi)cAMP水平(如forskolin或PDE4B特異性抑制劑處理DLBCL細(xì)胞)不僅可以抑制細(xì)胞內(nèi)AKT通路活化,而且能夠提高細(xì)胞內(nèi)糖皮質(zhì)激素受體表達(dá),從而增強DLBCL細(xì)胞對糖皮質(zhì)激素的敏感性[12]。因此,提高DLBCL細(xì)胞內(nèi)cAMP水平不僅可以直接介導(dǎo)其細(xì)胞生長阻滯和凋亡,而且能夠增強糖皮質(zhì)激素的凋亡誘導(dǎo)效應(yīng)或逆轉(zhuǎn)激素耐藥。
相對于DLBCL,慢性淋巴細(xì)胞白血病/小淋巴細(xì)胞淋巴瘤(chronic lymphocytic leukemia/ small lymphocyte lymphoma,CLL/SLL)臨床呈惰性進程,現(xiàn)有細(xì)胞毒化療藥物聯(lián)合免疫治療雖然可以誘導(dǎo)CLL臨床緩解,但仍無法治愈該疾?。?3]。因此,有必要尋找針對復(fù)發(fā)或難治性CLL有效治療途徑。Mentz研究小組最先報道,PDE抑制劑茶堿能夠誘導(dǎo)CLL細(xì)胞凋亡,而且該效應(yīng)能被cAMP拮抗劑部分逆轉(zhuǎn),提示茶堿介導(dǎo)CLL凋亡與其提高CLL細(xì)胞內(nèi)cAMP水平密切相關(guān)[14]。但同樣濃度的茶堿對正常B淋巴細(xì)胞活力無顯著影響。隨后多個體外研究結(jié)果也證實,茶堿可以誘導(dǎo)CLL細(xì)胞凋亡,而且其他提高細(xì)胞內(nèi)cAMP水平的藥物(如AC激動劑forskolin等)能增強茶堿的凋亡誘導(dǎo)效應(yīng)[15]。為了更有效并且特異性提高CLL細(xì)胞內(nèi)cAMP水平而介導(dǎo)其凋亡,篩選CLL細(xì)胞內(nèi)PDE亞型特異性抑制劑成為研究重點。隨后酶學(xué)和分子生物學(xué)研究提示,PDE4特異性抑制劑rolipram能夠有效而穩(wěn)定誘導(dǎo)原代CLL細(xì)胞凋亡,而且該效應(yīng)與其提高CLL細(xì)胞內(nèi)cAMP水平密切相關(guān)[16]。此外,rolipram對外周正常T和B淋巴細(xì)胞活力影響較小,推測與PDE4細(xì)胞內(nèi)亞定位相關(guān)(正常T和B淋巴細(xì)胞與CLL細(xì)胞內(nèi)PDE4定位不同導(dǎo)致cAMP調(diào)控分子分布和最終細(xì)胞生物學(xué)效應(yīng)的差異)。
T細(xì)胞淋巴瘤雖然發(fā)病率較低,但其對傳統(tǒng)化療藥物敏感性較低而預(yù)后較差。設(shè)計針對T細(xì)胞淋巴瘤特異性新型治療模式有其重要臨床意義。Coffino等[17]首先報道,cAMP擬似物或提高細(xì)胞內(nèi)cAMP藥物(如PDE抑制劑茶堿或G蛋白偶聯(lián)受體激動劑等)能夠誘導(dǎo)小鼠T淋巴瘤細(xì)胞株S49細(xì)胞凋亡。隨后的研究證實,cAMP擬似物能夠介導(dǎo)T淋巴瘤細(xì)胞生長G1期阻滯和凋亡特征性變化(DNA片段等)[18]。此外,通過細(xì)胞培養(yǎng)克隆了cAMP耐藥S49細(xì)胞亞型Kin-S49(PKA缺乏或功能缺陷S49細(xì)胞)和D-S49(具備正常PKA活性但缺乏cAMP介導(dǎo)細(xì)胞凋亡的S49細(xì)胞)。這些耐藥S49細(xì)胞株聯(lián)合野生型S49(wild type S49,WT-S49)細(xì)胞為深入探究調(diào)變cAMP信號通路誘導(dǎo)T細(xì)胞淋巴瘤凋亡提供了獨特和理想的實驗平臺。近年來,有研究還發(fā)現(xiàn),提高調(diào)節(jié)性T淋巴細(xì)胞內(nèi)cAMP水平能夠有效抑制其功能,從而解除調(diào)節(jié)性T淋巴細(xì)胞對效應(yīng)T淋巴細(xì)胞負(fù)向調(diào)控進而增強其對淋巴瘤細(xì)胞免疫攻擊[19]。因此,調(diào)變cAMP信號通路不僅可以誘導(dǎo)T淋巴瘤細(xì)胞凋亡,還能夠調(diào)控調(diào)節(jié)性T淋巴細(xì)胞功能而逆轉(zhuǎn)淋巴瘤細(xì)胞免疫逃逸。
細(xì)胞凋亡是細(xì)胞主動的程序性死亡過程,存在兩種基本凋亡途徑:① 內(nèi)源性線粒體依賴的凋亡途徑,主要涉及線粒體跨膜電位改變和去極化,細(xì)胞色素C和第二線粒體源性半胱天冬酶激活因子(second mitochondria-derived activator of caspase,Smac)釋放和下游內(nèi)源性caspase激活(caspase-9和caspase-3);② 外源性細(xì)胞膜受體介導(dǎo)的凋亡途徑,主要涉及細(xì)胞膜表面凋亡受體(如Fas受體等)活化和下游外源性caspase激活(caspase-8等)。其中內(nèi)源性凋亡途徑受B細(xì)胞淋巴瘤相關(guān)蛋白(B cell lymphoma-related proteins,Bcl-related proteins)調(diào)控,其中包括凋亡抑制蛋白(Bcl-2和BclXL等)和凋亡誘導(dǎo)蛋白(Bax、Bak、BAD、BIM和BclXS等)共同調(diào)控線粒體釋放細(xì)胞色素C等凋亡因子[20-21]。提高淋巴瘤細(xì)胞內(nèi)cAMP水平的藥物或制劑主要通過內(nèi)源性線粒體依賴的凋亡途徑誘導(dǎo)細(xì)胞凋亡。流式細(xì)胞儀檢測線粒體跨膜電位結(jié)果顯示,forskolin處理DLBCL細(xì)胞后,細(xì)胞內(nèi)線粒體跨膜電位明顯降低,同時伴隨細(xì)胞色素C釋放和下游caspase-9 及caspase-3活性增加[10]。小鼠T淋巴瘤細(xì)胞株S49實驗也顯示出相似結(jié)果。cAMP擬似物處理S49細(xì)胞后,細(xì)胞內(nèi)線粒體跨膜電位下降,隨后細(xì)胞色素C和Smac釋放,caspase-3活化,而外源性細(xì)胞凋亡途徑相關(guān)的caspase-8沒有被cAMP擬似物激活[7]。這些研究結(jié)果提示,cAMP信號通路主要通過線粒體途徑誘導(dǎo)淋巴瘤細(xì)胞凋亡。
cAMP下游直接效應(yīng)分子包括PKA和EPAC等。此外,cAMP還可對細(xì)胞內(nèi)其他信號通路產(chǎn)生間接影響。有研究發(fā)現(xiàn),cAMP擬似物無法誘導(dǎo)PKA缺乏或功能缺陷的Kin-S49細(xì)胞凋亡,而EPAC激動劑不能介導(dǎo)S49細(xì)胞凋亡[22]。這些結(jié)果提示,PKA是cAMP擬似物介導(dǎo)S49細(xì)胞凋亡的關(guān)鍵效應(yīng)分子。但DLBCL體外研究結(jié)果顯示,PKA特異性抑制劑H89或PKI雖然能夠有效抑制forskolin介導(dǎo)DLBCL細(xì)胞內(nèi)PKA活化,但對forskolin誘導(dǎo)細(xì)胞增殖阻滯和凋亡無顯著影響。此外,EPAC特異性激動劑對DLBCL細(xì)胞生長和活力無顯著影響,而forskolin能夠誘導(dǎo)缺乏EPAC的DLBCL細(xì)胞株DHL6細(xì)胞凋亡[10]。這些研究結(jié)果提示,cAMP介導(dǎo)的DLBCL細(xì)胞凋亡不依賴于PKA和EPAC。因此,cAMP下游直接效應(yīng)分子在不同淋巴瘤細(xì)胞凋亡中的作用大相徑庭。
Wilderman等[23]采用基因芯片技術(shù)比較WT-S49、Kin-S49和D-S49細(xì)胞在cAMP擬似物處理后基因表達(dá)譜的變化以明確cAMP信號通路介導(dǎo)淋巴瘤細(xì)胞凋亡中的關(guān)鍵分子,結(jié)果發(fā)現(xiàn),凋亡誘導(dǎo)因子Bim在cAMP擬似物8-(4-Chlorophenylthio)adenosine 3': 5'-cyclic monophosphate(8-CPT-cAMP)處理后的WT-S49細(xì)胞內(nèi)表達(dá)明顯升高,敲除Bim基因顯著鈍化8-CPT-cAMP介導(dǎo)的WT-S49細(xì)胞凋亡,過表達(dá)BimL(Bim的一種亞型)明顯提高8-CPT-cAMP介導(dǎo)的WT-S49、Kin-S49和D-S49細(xì)胞凋亡。這些結(jié)果提示,Bim是cAMP信號通路介導(dǎo)S49淋巴瘤細(xì)胞凋亡的關(guān)鍵分子。此外,細(xì)胞毒T淋巴細(xì)胞抗原-2(cytotoxic T lymphocyte antigen-2,CTLA-2)及生存素在cAMP介導(dǎo)S49細(xì)胞凋亡中也發(fā)揮關(guān)鍵作用[24]。但cAMP信號通路促發(fā)S49細(xì)胞凋亡的啟動關(guān)鍵分子及cAMP調(diào)控Bim和CTLA-2等因子的具體機制仍有待進一步明確。同時,DLBCL體外研究結(jié)果顯示,cAMP信號通路通過調(diào)變凋亡誘導(dǎo)因子BAD介導(dǎo)DLBCL細(xì)胞凋亡,cAMP信號通路通過抑制DLBCL細(xì)胞內(nèi)PI3K/AKT通路激活,繼而阻止AKT對其下游底物(包括BAD等)磷酸化,從而提高BAD活性介導(dǎo)細(xì)胞凋亡[12]。但cAMP信號通路調(diào)變PI3K活性的具體機制仍不明確,可能與cAMP直接或間接調(diào)控PI3K上游酪氨酸激酶(如RAS等)活性有關(guān)。
綜上所述,cAMP信號通路可能通過以下機制誘導(dǎo)淋巴瘤細(xì)胞凋亡:① 誘導(dǎo)淋巴瘤細(xì)胞內(nèi)線粒體跨膜電位下降和凋亡誘導(dǎo)因子釋放;②通過cAMP下游直接效應(yīng)分子PKA調(diào)變凋亡調(diào)控因子(如Bim和CTLA-2等)介導(dǎo)細(xì)胞凋亡;③ 直接或間接影響細(xì)胞內(nèi)其他信號通路(如PI3K/AKT通路等)進而調(diào)變凋亡相關(guān)因子(如BAD等)誘導(dǎo)細(xì)胞凋亡。
調(diào)變淋巴瘤細(xì)胞內(nèi)cAMP信號通路的可能方式包括活化淋巴瘤細(xì)胞內(nèi)AC、抑制細(xì)胞內(nèi)cAMP降解和直接針對cAMP通路的效應(yīng)分子。
首先,應(yīng)用受體激動劑增強淋巴瘤細(xì)胞內(nèi)AC活性可能產(chǎn)生非靶器官組織細(xì)胞因AC亢進而導(dǎo)致不良反應(yīng),因此,如何瞬時提高淋巴瘤細(xì)胞內(nèi)AC活性而達(dá)到治療目的同時不顯著影響其正常組織器官成為治療關(guān)鍵。G蛋白偶聯(lián)受體激動劑前列腺素E2能夠通過提高CLL細(xì)胞內(nèi)cAMP水平而誘導(dǎo)其凋亡,使其具備臨床應(yīng)用前景[15]。
其次,抑制淋巴瘤細(xì)胞內(nèi)cAMP降解藥物包括非特異性和亞型特異性PDE抑制劑,目前針對淋巴瘤細(xì)胞的PDE亞型抑制劑包括PDE1、PDE3、PDE4和PDE7抑制劑?;隗w外研究結(jié)果,Willis等[25]應(yīng)用茶堿聯(lián)合苯丁酸氮芥治療復(fù)發(fā)或難治性CLL,10例患者中9例臨床應(yīng)答,其中5例獲得臨床緩解。而PDE4特異性抑制劑rolipram已成功應(yīng)用于支氣管哮喘和自身免疫性腦脊髓膜炎等疾病治療,具備良好臨床應(yīng)用安全性。針對14例CLL患者原代細(xì)胞敏感性檢測顯示,rolipram誘導(dǎo)CLL細(xì)胞凋亡率為34%~89%,并且與CLL患者臨床分期及既往化療反應(yīng)無關(guān),顯示出良好臨床應(yīng)用潛力[16]。
最后,直接針對cAMP通路調(diào)控的效應(yīng)分子介導(dǎo)淋巴瘤細(xì)胞凋亡也是有效的治療策略。cAMP下游效應(yīng)分子PKA在cAMP介導(dǎo)的T淋巴瘤細(xì)胞凋亡發(fā)揮關(guān)鍵作用。因此,PKA特異性cAMP擬似物存在應(yīng)用于T淋巴瘤治療的可能性。此外,在cAMP介導(dǎo)DLBCL細(xì)胞凋亡中關(guān)鍵分子PI3K/AKT也是重要治療靶標(biāo)。PI3K特異性抑制劑idelalisib已成功應(yīng)用于惰性淋巴瘤治療。隨機和前瞻性研究顯示,idelalisib聯(lián)合利妥昔單抗治療復(fù)發(fā)CLL總有效率達(dá)81%,中位無疾病進展生存時間未達(dá)到,提示大部分患者仍存活。此外,PI3K特異性抑制劑對難治性CLL患者(尤其是P53基因缺失患者)顯示出良好療效[26]。
總之,調(diào)變cAMP信號通路可以誘導(dǎo)淋巴瘤細(xì)胞增殖阻滯和凋亡,其機制涉及淋巴瘤細(xì)胞內(nèi)線粒體跨膜電位下降、cAMP調(diào)控蛋白激酶PKA和多種細(xì)胞內(nèi)調(diào)控因子。隨著對cAMP介導(dǎo)淋巴瘤細(xì)胞凋亡深入研究分析,找到參與cAMP信號通路誘導(dǎo)淋巴瘤細(xì)胞凋亡的關(guān)鍵分子或途徑,將為臨床治療淋巴瘤提供潛在靶標(biāo)和新型治療途徑。
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DOI:10.19401/j.cnki.1007-3639.2016.06.013
中圖分類號:R733.4
文獻標(biāo)志碼:A
文章編號:1007-3639(2016)06-0556-05
收稿日期:(2016-01-05 修回日期:2016-03-15)
基金項目:上海市自然基金(13ZR1423800)。
通信作者:朱 琦 E-mail: zhuqi70@hotmail.com
Lymphoma and cAMP signaling pathway
ZHONG Yao, ZHU Qi
(Department of Hematology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China)Correspondence to: ZHU Qi E-mail: zhuqi70@hotmail.com
[Abstract]Several signaling pathways are involved in clonal proliferation of lymphoma cells and disease progression. It has been shown that cyclic adenosine monophosphate (cAMP) signaling pathway, as an important intracellular messenger delivery system, is related to modulation of multiple physiological processes including cell proliferation, secretion, metabolism and apoptosis. Manipulating the cAMP signaling pathway can induce cell cycle arrest and apoptosis of various malignant lymphoid cells, which involves mitochondria-dependent apoptosis and cAMP-modulated protein kinases as well as changes of intracellular mediators. In-depth research and analysis of cAMP-induced apoptosis in lymphoma cells would provide potential targets and possible therapeutic means for the treatment of lymphoma.
[Key words]Lymphoma; Cyclic adenosine monophosphate signaling pathway; Apoptosis