PPARα激动剂（非诺贝特）在胰腺癌治疗中的应用及可能的作用机制
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摘要
研究背景:
胰腺癌恶性程度高,在北美和欧洲分别位居恶性肿瘤死亡的第4位和第6位,在我国也长期位列前10位。据统计全球每年约有227,023人因胰腺癌导致死亡。胰腺癌发病隐匿,早期诊断困难,只有10%-15%的患者就诊时具有手术切除机会。即使进行了手术切除,还有相当一部分病人术后发生复发和转移,因此单纯的手术治疗无法取得理想的效果。化疗是目前最主要的辅助治疗手段,尤其针对中晚期胰腺癌患者。健择作为胰腺癌一线化疗药物,对改善症状、延长生存均起到了积极作用。然而由于天然内在性或后天获得性耐药,胰腺癌病人对健择的总体有效率仍不到20%,所以探索新的治疗方案十分必要。
过氧化物酶体增殖因子激活受体α(Peroxisome Proliferator-activated Receptorα,PPARα)是一类由配体激活的转录因子,属于核激素受体超家族成员。PPARα激动剂非诺贝特(Fenofibrate)是目前临床上用于降血脂的药物,它可以降低极低密度脂蛋白和低密度脂蛋白的合成,加速甘油三酯的代谢。最新研究表明PPARα激动剂对人体肝癌细胞、子宫内膜癌细胞、卵巢癌细胞和结肠癌细胞具有显著的抗肿瘤活性。对人体胰腺癌细胞,PPARα激动剂是否具有类似的抗肿瘤功效目前还未见相关报道。本课题通过一系列实验探讨了PPARα激动剂非诺贝特以及联用非诺贝特和健择对人体胰腺癌细胞生长与转移的影响。
磷脂酰肌醇3-激酶/蛋白激酶B(Phosphatidylinositol 3-Kinase/Protein Kinase B,PI3K/Akt)信号通路广泛存在于细胞内,被认为与肿瘤细胞的增殖、凋亡和转移等多个事件密切相关,是连接外界信号分子和细胞内反应的纽带。我们使用RT-PCR和Western blot等技术探讨了Akt信号通路在非诺贝特治疗胰腺癌过程中所扮演的角色,为将来以PPARα为靶点防治胰腺癌提供理论基础及实验依据。
第一部分PPARα激动剂(非诺贝特)抑制胰腺癌生长及可能的分子机制
目的:
观察PPARα在人体胰腺癌组织和胰腺癌细胞株的表达情况,检测PPARα激动剂非诺贝特以及联用非诺贝特和健择对人体胰腺癌细胞增殖、凋亡等生物学行为的影响,并从分子水平探讨其可能的作用机制。
方法:
(1)采用免疫组化,RT-PCR和Western blot等技术检测了PPARα在人体胰腺癌组织和胰腺癌细胞株的表达情况。
(2)使用MTT、流式细胞仪分析和Hoechst 33258染色等方法于体外观察单用非诺贝特以及联用非诺贝特与健择对胰腺癌细胞株Bxpc-3和Panc-1增殖、凋亡等生物学行为的影响。
(3)建立荷瘤鼠模型于体内测试了非诺贝特以及联用非诺贝特和健择对胰腺癌生长的抑制作用;增殖细胞核抗原(PCNA)染色、缺口末端标记法(TUNEL)和CD31染色在病理学水平检测了不同给药组瘤块增殖率、凋亡率及微血管密度的差异。
(4)Western blot实验检测不同药物干预下胰腺癌细胞内凋亡相关蛋白Caspase-9、Caspase-3和Bcl-2的表达水平。
(5)Western blot实验检测不同药物干预下胰腺癌细胞内TRB-3、Akt、phospho-Akt和Survivin等蛋白的表达变化。
结果:
(1)免疫组化检测9例胰腺癌病人的标本,结果6例样本PPARα呈高表达,3例样本PPARα呈低表达,染色以胞浆阳性为主;RT-PCR和Western blot实验证实胰腺癌细胞株Bxpc-3和Panc-1都表达PPARα基因。
(2)MTT实验发现PPARα激动剂非诺贝特呈剂量依赖性的抑制胰腺癌细胞生长。对Bxpc-3,25μM非诺贝特作用48小时细胞增殖率为53.1±5.6%,25μM非诺贝特和0.5μg/ml健择联用48小时细胞增殖率仅为36.3±3.9%,联合用药组细胞增殖率显著低于单药组(P＜0.05);对Panc-1,50μM非诺贝特作用48小时细胞增殖率为67.5±2.4%,50μM非诺贝特和5μg/ml健择联用48小时细胞增殖率仅为53.5±7.9%,联合用药组细胞增殖率也显著低于单药组(P＜0.05)。
(3)流式细胞仪分析得两药联用(非诺贝特+健择)处理48小时胰腺癌细胞凋亡率明显高于对照组或单药组(P＜0.05)。
(4)光镜及Hoechst 33258染色观察到非诺贝特作用下胰腺癌细胞体积变小,部分细胞的胞膜崩解,细胞核变小,呈致密浓染,并伴碎块状的凋亡小体,两药联用组碎块状的凋亡小体多于单药组。
(5)成功建立Bxpc-3细胞的荷瘤鼠模型,把荷瘤鼠随机分成对照组(给予生理盐水)、单用非诺贝特组、单用健择组和非诺贝特联用健择组;给药3周后,与对照组相比,单用非诺贝特或健择组肿瘤体积减小,联合用药组比单药组减小的更明显。以PCNA的阳性率作为增殖指数,免疫组化结果显示两药联用组肿瘤细胞增殖指数为61.7±5.2%,显著低于对照组的84.3±3.5%(P＜0.05)。TUNEL法检测了不同给药组之间细胞凋亡率的差异,对照组凋亡指数为0.8±0.3%,单用非诺贝特组凋亡指数为7.3±1.1%,单用健择组凋亡指数为4.3±0.9%,非诺贝特和健择联用组凋亡指数为13.3±1.8%,联合用药组的凋亡指数显著高于对照组和单药组(P＜0.05)。CD31染色显示两药联用组微血管密度低于对照组,但两者之间无统计学差异。
(6)Western blot实验发现单用非诺贝特或健择干预48小时,胰腺癌细胞内抗凋亡蛋白Bcl-2的表达水平下降,凋亡蛋白Caspase-9、Caspase-3的活性剪切片断出现;联用非诺贝特和健择进一步下调了Bcl-2的表达水平,而Caspase-9、Caspase-3的活性剪切片断更加明显。
(7)Western blot实验显示PPARα激动剂非诺贝特干预24小时后胰腺癌细胞中TRB-3蛋白上调,而Akt的磷酸化程度和凋亡蛋白抑制因子Survivin的表达量都有明显下调;单用健择处理24小时Akt的磷酸化程度和Survivin的表达量变化不明显。
结论:
(1)人体胰腺癌组织和细胞株都表达PPARα蛋白。
(2)PPARα激动剂非诺贝特能有效抑制胰腺癌细胞生长,联用非诺贝特和健择进一步增强了对胰腺癌细胞的生长抑制效应。
(3)非诺贝特能诱导胰腺癌细胞发生凋亡,联用非诺贝特和健择进一步提高了诱导细胞凋亡的能力。
(4)对胰腺癌细胞,PPARα激动剂非诺贝特可能通过上调TRB-3蛋白水平,降低了Akt的磷酸化程度,并激活凋亡蛋白Caspase-9和Caspase-3,下调抗凋亡蛋白Bcl-2和Survivin的表达量,最终引起细胞凋亡。
第二部分非诺贝特抑制胰腺癌细胞迁移及可能的作用机制
目的:
观察PPARα激动剂非诺贝特以及联用非诺贝特和健择对人体胰腺癌细胞迁移能力的影响,并从分子水平探讨其可能的作用机制。
方法:
(1)细胞划痕试验定性观察不同药物处理对胰腺癌细胞迁移能力的影响。
(2)Transwell细胞迁移实验定量检测胰腺癌细胞在不同药物处理下迁移能力的变化。
(3)RT-PCR检测不同药物干预下胰腺癌细胞中E-cadherin和Snail在mRNA水平的变化。
(4)Western blot检测不同药物处理后胰腺癌细胞株中E-cadherin、Snail和phospho-GSK3β蛋白水平的变化。
结果:
(1)细胞划痕试验显示:不同药物作用胰腺癌细胞24小时,阴性对照组细胞已接近愈合;单用非诺贝特组和两药联用组可见少量细胞向划痕区爬行,愈合程度远低于阴性对照组;单用健择组有大量细胞向划痕区爬行,愈合程度略低于阴性对照组。
(2)Transwell细胞迁移试验示:以阴性对照组作参照,阴性对照组细胞迁移指数定为100%;对Bxpc-3,单用非诺贝特处理24小时细胞迁移指数为39.9±3.7%,单用健择处理24小时细胞迁移指数为91.6±2.3%,联用非诺贝特和健择处理24小时细胞迁移指数为35.7±4.6%,单用非诺贝特组和两药联用组的细胞迁移指数显著低于阴性对照组(P＜0.05);在另一株胰腺癌细胞Panc-1中也得到了类似结果。
(3)RT-PCR显示:与阴性对照组相比,单用非诺贝特处理24小时,胰腺癌细胞中E-cadherin的mRNA表达增高,而Snail的mRNA表达下降;单用健择处理24小时,E-cadherin和Snail在mRNA水平变化不明显;两药联用组E-cadherin和Snail在mRNA水平的变化与单用非诺贝特组类似。
(4)Western blot实验证实:单用非诺贝特处理24小时,胰腺癌细胞内E-cadherin蛋白条带比阴性对照组有一定程度的增强,Snail蛋白条带则相对减弱;健择干预24小时,E-cadherin和Snail的蛋白条带与阴性对照组相比无明显差异;两药联用时上述蛋白条带的变化趋势与单用非诺贝特基本类似。
(5)Western blot实验进一步检测发现:单用非诺贝特或两药联用干预24小时,胰腺癌细胞中GSK3β磷酸化水平下调,单用健择对GSK3β的磷酸化水平无明显影响。
结论:
(1)非诺贝特具有抑制人体胰腺癌细胞迁移的功效。
(2)非诺贝特可能通过降低胰腺癌细胞内Akt和底物GSK3β的磷酸化程度,活化了的GSK3β抑制Snail的表达,继而上调E-cadherin的表达量来实现抑制胰腺癌细胞迁移的。
Background:
Pancreatic cancer is the fourth most common cause of adult cancer death in the U.S. 232,306 people were expected to develop pancreatic cancer,with 227,023 anticipated deaths resulting from this disease.Pancreatic cancer is a highly aggressive malignant disease.Only a small proportion of patients(10%-15%) presented with tumors amenable to surgical resection,but even with surgery,disease recurrence will occur in the majority.Despite therapeutic advances,the prognosis of patients with pancreatic cancer is extremely poor,with 5-year survival of＜5%.Chemotherapy for pancreatic cancer is only of modest benefit,with the tumor having propensity to being chemoresistant.Gemcitabine has become the standard treatment for pancreatic cancer, since it was shown to improve clinical benefit response and survival compared with 5-fluorouracil(5-FU).Although superior to bolus 5-FU,the efficacy of gemcitabine as a single agent is modest,with a median survival of only～6 months in randomized trials and a 12-month survival of＜20%.Therefore,developing more effective treatment regimens is urgently needed.
Peroxisome proliferator-activated receptorα(PPARα) is a ligand-inducible transcription factor that belongs to the nuclear-hormone-receptor family.PPARαwas shown to mediate peroxisome proliferation action.PPARαagonist fenofibrate is mainly used in the treatment of dyslipidaemia.Recently,growing evidence indicated that PPARαagonist fenofibrate had antitumor effects,probably because of its anti-proliferative and pro-apoptotic activities.Reports published so far convincingly showed that fenofibrate inhibited proliferation of hepatic cancer cell lines,colon cancer cell lines,endometrical cancer cell lines and ovarian caner cell lines.However,there is no report concerning the antitumor efficacy of fenofibrate on pancreatic cancer cells.To improve the chemotherapeutic response,we investigated the potential of fenofibrate to augment gemcitabine-based chemotherapy for pancreatic cancer.Furthermore,we examined whether fenofibrate could inhibit the metastasis of pancreatic cancer.
Cancer progression is often associated with prolonged activation of signal transduction pathways,such as phosphatidylinositol 3-kinase/Akt(PI3K/Akt) pathway. This constitutive activation confers resistance to conventional therapeutics.Many papers reported that most human pancreatic tumors showed high levels of activated Akt, a serine/threonine protein kinase that mediates survival signaling.Akt phosphorylates and inactivates numerous pro-apoptotic proteins,such as BAD,caspase-9 and survivin. The progression from an in situ tumor to an invasive disseminating form requires profound changes in the tumor cell phenotype(e.g.gaining the ability to migrate,to intravasate and survive in the anchorage-independent conditions in blood vessels,and to penetrate distant organs).Based on these facts,we hypothesized that the inhibition of PI3K/Akt pathway might be involved in pro-apoptotic and antimetastatic activity of fenofibrate.
Part One The Anti-proliferative Effect of Fenofibrate on Pancreatic Cancer Cells and Relevant Mechanisms
Objective:
We attempted to evaluate whether cell growth and apoptosis are affected by PPARαagonist fenofibrate.
Materials and Methods:
(1) Sections of formalin-fixed and paraffin embedded material from pancreatic cancer patients were analyzed to detect PPARα-specific immunoreactivity.RT-PCR and western blot assays were done to detect PPARαexpression in pancreatic cancer cell lines Bxpc-3 and Panc-1.
(2) MTT assay was performed to analyze the anti-proliferative effect of fenofibrate and combined use of fenofibrate and gemcitabine on pancreatic cancer cell lines.
(3) The detection of apoptotic cells by flow cytometry was done to evaluate the pro-apoptotic effect of fenofibrate on pancreatic cancer cell lines.
(4) Hoechst 33258 staining was used to observe the apoptotic characteristics of pancreatic cancer cell lines with different therapeutic regimens.
(5) Nude mice were implanted with pancreatic cancer cells and randomized into the following treatment groups:(a) control(normal saline),(b) only fenofibrate,(c) only gemcitabine,(d) fenofibrate and gemcitabine.PCNA staining,TUNEL and CD31 staining were used to estimate the proliferation,apoptosis and microvessel density in tumor tissues.
(6) Western blot analysis was done to detect Bcl-2,caspase-9,caspase-3 in the pancreatic cancer cells with various treatment schedules.
(7) Western blotting was performed to evaluate Akt,phospho-Akt and survivin in pancreatic cancer cells treated with different regimens.
Results:
(1) High PPARαexpression was detected in 6 of 9 pancreatic cancers.Pancreatic cancer cell lines Bxpc-3 and Panc-1 also expressed PPARα.
(2) Fenofibrate inhibited growth of pancreatic cancer cells in a dose- and time-dependent manner.In Bxpc-3 cells,treatment with 25μM fenofibrate for 48 hours resulted in 53.1±5.6%cell growth relative to the control.In Panc-1,treatment with 50μM fenofibrate for 48 hours resulted in 67.5±2.4%cell growth relative to the control. We subsequently evaluated the effect of fenofibrate plus gemcitabine on cell growth in vitro and found that combined use of fenofibrate and gemcitabine enhanced the anti-proliferative activity.
(3) As shown by flow cytometry,fenofibrate could induce apoptosis in pancreatic cancer cells.Relative to single agents,cotreatment of fenofibrate and gemcitabine induced much more apoptosis in both pancreatic cancer cell lines(P＜0.05).
(4) Hoechst 33258 staining demonstrated characteristics of apoptosis in cells receiving fenofibrate and/or gemcitabine treatment.
(5) For in vivo experiments,we determined the mean tumor volume in all treated groups.Single modality treatment with either fenofibrate or gemcitabine alone in mice harboring Bxpc-3 cells caused reduction in tumor volume compared with normal saline treatment after 3 weeks.Treatment with fenofibrate plus gemcitabine simultaneously resulted in greater reduction in tumor volume compared with control tumors.We next examined the expression of the cell proliferation marker PCNA and microvessel density marker CD31 in tumor tissues from the four groups.The results showed that fenofibrate in combination with gemcitabine significantly down-regulated the expression of PCNA in tumors tissues compared with the control group(P＜0.05 versus control).The data also showed that fenofibrate suppressed the expression of CD31,but the down-regulation was not statistically different.TUNEL demonstrated that fenofibrate could enhance the induction of apoptosis by gemcitabine.Cotreatment of fenofibrate and gemcitabine induced more apoptotic cells than single agent either fenofibrate or gemcitabine alone(P＜0.05).
(6) Western blotting revealed significant reduction in the expression of Bcl-2 from the fenofibrate-treated pancreatic cancer cell lines compared with those from the control group.The expression of cleaved caspase-9 and cleaved caspase-3 increased with the treatment of fenofibrate.
(7) Up-regulation of TRB-3 was noticed in pancreatic cancer cell lines with fenofibrate treatment.In the next step,we observed down-regulation of phosphorylation status of Akt after incubation with fenofibrate without a change in total Akt protein level. Similar down-regulation in survivin was detected after fenofibrate treatment.
Conclusions:
(1) Pancreatic cancer specimens and cell lines expressed PPARα.
(2) Fenofibrate inhibited pancreatic cancer cells growth in a dose- and time-dependent manner.Combined treatment of fenofibrate and gemcitabine resulted in greater inhibition of cell growth.
(3) Fenofibrate induced apoptosis of pancreatic cancer cells and treatment of fenofibrate plus gemcitabine potentiated the pro-apoptotic effects.
(4) Fenofibrate decreased the phosphorylation status of Akt and expression of survivin via up-regulation of TRB-3.
Part Two The Inhibitory Effect of Fenofibrate on Migration of Pancreatic Cancer Cells and Relevant Mechanisms
Objective:
We attempted to evaluate whether migration of pancreatic caner cells was affected by fenofibrate.
Materials and Methods:
(1) We used wound-healing assay to estimate the effect of fenofibrate on migration ability of pancreatic cancer cells.
(2) Cell migration was assessed quantitatively in Transwell chambers with polycarbonate filters.
(3) RT-PCR was used to determine the expression of E-cadherin and snail in pancreatic cancer cell lines incubated with different therapeutic modalities.
(4) Western blotting was done to detect E-cadherin,snail and phospho-GSK3βin pancreatic cancer cells after treatment with various agents.
Results:
(1) Wound gap was almost closed in control group after 24 hours wound introduction.In contrast,the speed of wound closure was much slower and the wounds were still widely open in the fenofibrate-treated group.
(2) Transwell chamber showed that the migration index in the presence of fenofibrate was 39.9±3.7%,significantly lower than the control group(P＜0.05). Gemcitabine did not cause significant decrease of migration index.
(3) RT-PCR results demonstrated that E-cadherin was up-regulated and snail was down-regulated after the fenofibrate treatment.The expression level of E-cadherin and snail was not affected by gemcitabine.
(4) Western blotting further confirmed that expression of E-cadherin increased and expression of snail decreased simultaneously in the fenofibrate-treated group.The protein levels of E-cadherin and snail remained similar after gemcitabine treatment compared with the control group.
(5) Down-regulation of phosphorylation status of GSK3βwas observed from the fenofibrate-treated group.
Conclusions:
(1) Fenofibrate inhibited migration of pancreatic cancer cells.
(2) Fenofibrate treatment led to impaired migration ability of pancreatic cancer cells via the attenuation of Akt/GSK3βmediated pathway.The decreased phosphorylation level of GSK3βrestored its kinase activity and subsequently blocked snail expression. Finally,the E-cadherin protein accumulated in pancreatic cancer cells treated with fenofibrate.
胰腺癌恶性程度高,在北美和欧洲分别位居恶性肿瘤死亡的第4位和第6位,在我国也长期位列前10位。据统计全球每年约有227,023人因胰腺癌导致死亡。胰腺癌发病隐匿,早期诊断困难,只有10%-15%的患者就诊时具有手术切除机会。即使进行了手术切除,还有相当一部分病人术后发生复发和转移,因此单纯的手术治疗无法取得理想的效果。化疗是目前最主要的辅助治疗手段,尤其针对中晚期胰腺癌患者。健择作为胰腺癌一线化疗药物,对改善症状、延长生存均起到了积极作用。然而由于天然内在性或后天获得性耐药,胰腺癌病人对健择的总体有效率仍不到20%,所以探索新的治疗方案十分必要。
过氧化物酶体增殖因子激活受体α(Peroxisome Proliferator-activated Receptorα,PPARα)是一类由配体激活的转录因子,属于核激素受体超家族成员。PPARα激动剂非诺贝特(Fenofibrate)是目前临床上用于降血脂的药物,它可以降低极低密度脂蛋白和低密度脂蛋白的合成,加速甘油三酯的代谢。最新研究表明PPARα激动剂对人体肝癌细胞、子宫内膜癌细胞、卵巢癌细胞和结肠癌细胞具有显著的抗肿瘤活性。对人体胰腺癌细胞,PPARα激动剂是否具有类似的抗肿瘤功效目前还未见相关报道。本课题通过一系列实验探讨了PPARα激动剂非诺贝特以及联用非诺贝特和健择对人体胰腺癌细胞生长与转移的影响。
磷脂酰肌醇3-激酶/蛋白激酶B(Phosphatidylinositol 3-Kinase/Protein Kinase B,PI3K/Akt)信号通路广泛存在于细胞内,被认为与肿瘤细胞的增殖、凋亡和转移等多个事件密切相关,是连接外界信号分子和细胞内反应的纽带。我们使用RT-PCR和Western blot等技术探讨了Akt信号通路在非诺贝特治疗胰腺癌过程中所扮演的角色,为将来以PPARα为靶点防治胰腺癌提供理论基础及实验依据。
第一部分PPARα激动剂(非诺贝特)抑制胰腺癌生长及可能的分子机制
目的:
观察PPARα在人体胰腺癌组织和胰腺癌细胞株的表达情况,检测PPARα激动剂非诺贝特以及联用非诺贝特和健择对人体胰腺癌细胞增殖、凋亡等生物学行为的影响,并从分子水平探讨其可能的作用机制。
方法:
(1)采用免疫组化,RT-PCR和Western blot等技术检测了PPARα在人体胰腺癌组织和胰腺癌细胞株的表达情况。
(2)使用MTT、流式细胞仪分析和Hoechst 33258染色等方法于体外观察单用非诺贝特以及联用非诺贝特与健择对胰腺癌细胞株Bxpc-3和Panc-1增殖、凋亡等生物学行为的影响。
(3)建立荷瘤鼠模型于体内测试了非诺贝特以及联用非诺贝特和健择对胰腺癌生长的抑制作用;增殖细胞核抗原(PCNA)染色、缺口末端标记法(TUNEL)和CD31染色在病理学水平检测了不同给药组瘤块增殖率、凋亡率及微血管密度的差异。
(4)Western blot实验检测不同药物干预下胰腺癌细胞内凋亡相关蛋白Caspase-9、Caspase-3和Bcl-2的表达水平。
(5)Western blot实验检测不同药物干预下胰腺癌细胞内TRB-3、Akt、phospho-Akt和Survivin等蛋白的表达变化。
结果:
(1)免疫组化检测9例胰腺癌病人的标本,结果6例样本PPARα呈高表达,3例样本PPARα呈低表达,染色以胞浆阳性为主;RT-PCR和Western blot实验证实胰腺癌细胞株Bxpc-3和Panc-1都表达PPARα基因。
(2)MTT实验发现PPARα激动剂非诺贝特呈剂量依赖性的抑制胰腺癌细胞生长。对Bxpc-3,25μM非诺贝特作用48小时细胞增殖率为53.1±5.6%,25μM非诺贝特和0.5μg/ml健择联用48小时细胞增殖率仅为36.3±3.9%,联合用药组细胞增殖率显著低于单药组(P＜0.05);对Panc-1,50μM非诺贝特作用48小时细胞增殖率为67.5±2.4%,50μM非诺贝特和5μg/ml健择联用48小时细胞增殖率仅为53.5±7.9%,联合用药组细胞增殖率也显著低于单药组(P＜0.05)。
(3)流式细胞仪分析得两药联用(非诺贝特+健择)处理48小时胰腺癌细胞凋亡率明显高于对照组或单药组(P＜0.05)。
(4)光镜及Hoechst 33258染色观察到非诺贝特作用下胰腺癌细胞体积变小,部分细胞的胞膜崩解,细胞核变小,呈致密浓染,并伴碎块状的凋亡小体,两药联用组碎块状的凋亡小体多于单药组。
(5)成功建立Bxpc-3细胞的荷瘤鼠模型,把荷瘤鼠随机分成对照组(给予生理盐水)、单用非诺贝特组、单用健择组和非诺贝特联用健择组;给药3周后,与对照组相比,单用非诺贝特或健择组肿瘤体积减小,联合用药组比单药组减小的更明显。以PCNA的阳性率作为增殖指数,免疫组化结果显示两药联用组肿瘤细胞增殖指数为61.7±5.2%,显著低于对照组的84.3±3.5%(P＜0.05)。TUNEL法检测了不同给药组之间细胞凋亡率的差异,对照组凋亡指数为0.8±0.3%,单用非诺贝特组凋亡指数为7.3±1.1%,单用健择组凋亡指数为4.3±0.9%,非诺贝特和健择联用组凋亡指数为13.3±1.8%,联合用药组的凋亡指数显著高于对照组和单药组(P＜0.05)。CD31染色显示两药联用组微血管密度低于对照组,但两者之间无统计学差异。
(6)Western blot实验发现单用非诺贝特或健择干预48小时,胰腺癌细胞内抗凋亡蛋白Bcl-2的表达水平下降,凋亡蛋白Caspase-9、Caspase-3的活性剪切片断出现;联用非诺贝特和健择进一步下调了Bcl-2的表达水平,而Caspase-9、Caspase-3的活性剪切片断更加明显。
(7)Western blot实验显示PPARα激动剂非诺贝特干预24小时后胰腺癌细胞中TRB-3蛋白上调,而Akt的磷酸化程度和凋亡蛋白抑制因子Survivin的表达量都有明显下调;单用健择处理24小时Akt的磷酸化程度和Survivin的表达量变化不明显。
结论:
(1)人体胰腺癌组织和细胞株都表达PPARα蛋白。
(2)PPARα激动剂非诺贝特能有效抑制胰腺癌细胞生长,联用非诺贝特和健择进一步增强了对胰腺癌细胞的生长抑制效应。
(3)非诺贝特能诱导胰腺癌细胞发生凋亡,联用非诺贝特和健择进一步提高了诱导细胞凋亡的能力。
(4)对胰腺癌细胞,PPARα激动剂非诺贝特可能通过上调TRB-3蛋白水平,降低了Akt的磷酸化程度,并激活凋亡蛋白Caspase-9和Caspase-3,下调抗凋亡蛋白Bcl-2和Survivin的表达量,最终引起细胞凋亡。
第二部分非诺贝特抑制胰腺癌细胞迁移及可能的作用机制
目的:
观察PPARα激动剂非诺贝特以及联用非诺贝特和健择对人体胰腺癌细胞迁移能力的影响,并从分子水平探讨其可能的作用机制。
方法:
(1)细胞划痕试验定性观察不同药物处理对胰腺癌细胞迁移能力的影响。
(2)Transwell细胞迁移实验定量检测胰腺癌细胞在不同药物处理下迁移能力的变化。
(3)RT-PCR检测不同药物干预下胰腺癌细胞中E-cadherin和Snail在mRNA水平的变化。
(4)Western blot检测不同药物处理后胰腺癌细胞株中E-cadherin、Snail和phospho-GSK3β蛋白水平的变化。
结果:
(1)细胞划痕试验显示:不同药物作用胰腺癌细胞24小时,阴性对照组细胞已接近愈合;单用非诺贝特组和两药联用组可见少量细胞向划痕区爬行,愈合程度远低于阴性对照组;单用健择组有大量细胞向划痕区爬行,愈合程度略低于阴性对照组。
(2)Transwell细胞迁移试验示:以阴性对照组作参照,阴性对照组细胞迁移指数定为100%;对Bxpc-3,单用非诺贝特处理24小时细胞迁移指数为39.9±3.7%,单用健择处理24小时细胞迁移指数为91.6±2.3%,联用非诺贝特和健择处理24小时细胞迁移指数为35.7±4.6%,单用非诺贝特组和两药联用组的细胞迁移指数显著低于阴性对照组(P＜0.05);在另一株胰腺癌细胞Panc-1中也得到了类似结果。
(3)RT-PCR显示:与阴性对照组相比,单用非诺贝特处理24小时,胰腺癌细胞中E-cadherin的mRNA表达增高,而Snail的mRNA表达下降;单用健择处理24小时,E-cadherin和Snail在mRNA水平变化不明显;两药联用组E-cadherin和Snail在mRNA水平的变化与单用非诺贝特组类似。
(4)Western blot实验证实:单用非诺贝特处理24小时,胰腺癌细胞内E-cadherin蛋白条带比阴性对照组有一定程度的增强,Snail蛋白条带则相对减弱;健择干预24小时,E-cadherin和Snail的蛋白条带与阴性对照组相比无明显差异;两药联用时上述蛋白条带的变化趋势与单用非诺贝特基本类似。
(5)Western blot实验进一步检测发现:单用非诺贝特或两药联用干预24小时,胰腺癌细胞中GSK3β磷酸化水平下调,单用健择对GSK3β的磷酸化水平无明显影响。
结论:
(1)非诺贝特具有抑制人体胰腺癌细胞迁移的功效。
(2)非诺贝特可能通过降低胰腺癌细胞内Akt和底物GSK3β的磷酸化程度,活化了的GSK3β抑制Snail的表达,继而上调E-cadherin的表达量来实现抑制胰腺癌细胞迁移的。
Background:
Pancreatic cancer is the fourth most common cause of adult cancer death in the U.S. 232,306 people were expected to develop pancreatic cancer,with 227,023 anticipated deaths resulting from this disease.Pancreatic cancer is a highly aggressive malignant disease.Only a small proportion of patients(10%-15%) presented with tumors amenable to surgical resection,but even with surgery,disease recurrence will occur in the majority.Despite therapeutic advances,the prognosis of patients with pancreatic cancer is extremely poor,with 5-year survival of＜5%.Chemotherapy for pancreatic cancer is only of modest benefit,with the tumor having propensity to being chemoresistant.Gemcitabine has become the standard treatment for pancreatic cancer, since it was shown to improve clinical benefit response and survival compared with 5-fluorouracil(5-FU).Although superior to bolus 5-FU,the efficacy of gemcitabine as a single agent is modest,with a median survival of only～6 months in randomized trials and a 12-month survival of＜20%.Therefore,developing more effective treatment regimens is urgently needed.
Peroxisome proliferator-activated receptorα(PPARα) is a ligand-inducible transcription factor that belongs to the nuclear-hormone-receptor family.PPARαwas shown to mediate peroxisome proliferation action.PPARαagonist fenofibrate is mainly used in the treatment of dyslipidaemia.Recently,growing evidence indicated that PPARαagonist fenofibrate had antitumor effects,probably because of its anti-proliferative and pro-apoptotic activities.Reports published so far convincingly showed that fenofibrate inhibited proliferation of hepatic cancer cell lines,colon cancer cell lines,endometrical cancer cell lines and ovarian caner cell lines.However,there is no report concerning the antitumor efficacy of fenofibrate on pancreatic cancer cells.To improve the chemotherapeutic response,we investigated the potential of fenofibrate to augment gemcitabine-based chemotherapy for pancreatic cancer.Furthermore,we examined whether fenofibrate could inhibit the metastasis of pancreatic cancer.
Cancer progression is often associated with prolonged activation of signal transduction pathways,such as phosphatidylinositol 3-kinase/Akt(PI3K/Akt) pathway. This constitutive activation confers resistance to conventional therapeutics.Many papers reported that most human pancreatic tumors showed high levels of activated Akt, a serine/threonine protein kinase that mediates survival signaling.Akt phosphorylates and inactivates numerous pro-apoptotic proteins,such as BAD,caspase-9 and survivin. The progression from an in situ tumor to an invasive disseminating form requires profound changes in the tumor cell phenotype(e.g.gaining the ability to migrate,to intravasate and survive in the anchorage-independent conditions in blood vessels,and to penetrate distant organs).Based on these facts,we hypothesized that the inhibition of PI3K/Akt pathway might be involved in pro-apoptotic and antimetastatic activity of fenofibrate.
Part One The Anti-proliferative Effect of Fenofibrate on Pancreatic Cancer Cells and Relevant Mechanisms
Objective:
We attempted to evaluate whether cell growth and apoptosis are affected by PPARαagonist fenofibrate.
Materials and Methods:
(1) Sections of formalin-fixed and paraffin embedded material from pancreatic cancer patients were analyzed to detect PPARα-specific immunoreactivity.RT-PCR and western blot assays were done to detect PPARαexpression in pancreatic cancer cell lines Bxpc-3 and Panc-1.
(2) MTT assay was performed to analyze the anti-proliferative effect of fenofibrate and combined use of fenofibrate and gemcitabine on pancreatic cancer cell lines.
(3) The detection of apoptotic cells by flow cytometry was done to evaluate the pro-apoptotic effect of fenofibrate on pancreatic cancer cell lines.
(4) Hoechst 33258 staining was used to observe the apoptotic characteristics of pancreatic cancer cell lines with different therapeutic regimens.
(5) Nude mice were implanted with pancreatic cancer cells and randomized into the following treatment groups:(a) control(normal saline),(b) only fenofibrate,(c) only gemcitabine,(d) fenofibrate and gemcitabine.PCNA staining,TUNEL and CD31 staining were used to estimate the proliferation,apoptosis and microvessel density in tumor tissues.
(6) Western blot analysis was done to detect Bcl-2,caspase-9,caspase-3 in the pancreatic cancer cells with various treatment schedules.
(7) Western blotting was performed to evaluate Akt,phospho-Akt and survivin in pancreatic cancer cells treated with different regimens.
Results:
(1) High PPARαexpression was detected in 6 of 9 pancreatic cancers.Pancreatic cancer cell lines Bxpc-3 and Panc-1 also expressed PPARα.
(2) Fenofibrate inhibited growth of pancreatic cancer cells in a dose- and time-dependent manner.In Bxpc-3 cells,treatment with 25μM fenofibrate for 48 hours resulted in 53.1±5.6%cell growth relative to the control.In Panc-1,treatment with 50μM fenofibrate for 48 hours resulted in 67.5±2.4%cell growth relative to the control. We subsequently evaluated the effect of fenofibrate plus gemcitabine on cell growth in vitro and found that combined use of fenofibrate and gemcitabine enhanced the anti-proliferative activity.
(3) As shown by flow cytometry,fenofibrate could induce apoptosis in pancreatic cancer cells.Relative to single agents,cotreatment of fenofibrate and gemcitabine induced much more apoptosis in both pancreatic cancer cell lines(P＜0.05).
(4) Hoechst 33258 staining demonstrated characteristics of apoptosis in cells receiving fenofibrate and/or gemcitabine treatment.
(5) For in vivo experiments,we determined the mean tumor volume in all treated groups.Single modality treatment with either fenofibrate or gemcitabine alone in mice harboring Bxpc-3 cells caused reduction in tumor volume compared with normal saline treatment after 3 weeks.Treatment with fenofibrate plus gemcitabine simultaneously resulted in greater reduction in tumor volume compared with control tumors.We next examined the expression of the cell proliferation marker PCNA and microvessel density marker CD31 in tumor tissues from the four groups.The results showed that fenofibrate in combination with gemcitabine significantly down-regulated the expression of PCNA in tumors tissues compared with the control group(P＜0.05 versus control).The data also showed that fenofibrate suppressed the expression of CD31,but the down-regulation was not statistically different.TUNEL demonstrated that fenofibrate could enhance the induction of apoptosis by gemcitabine.Cotreatment of fenofibrate and gemcitabine induced more apoptotic cells than single agent either fenofibrate or gemcitabine alone(P＜0.05).
(6) Western blotting revealed significant reduction in the expression of Bcl-2 from the fenofibrate-treated pancreatic cancer cell lines compared with those from the control group.The expression of cleaved caspase-9 and cleaved caspase-3 increased with the treatment of fenofibrate.
(7) Up-regulation of TRB-3 was noticed in pancreatic cancer cell lines with fenofibrate treatment.In the next step,we observed down-regulation of phosphorylation status of Akt after incubation with fenofibrate without a change in total Akt protein level. Similar down-regulation in survivin was detected after fenofibrate treatment.
Conclusions:
(1) Pancreatic cancer specimens and cell lines expressed PPARα.
(2) Fenofibrate inhibited pancreatic cancer cells growth in a dose- and time-dependent manner.Combined treatment of fenofibrate and gemcitabine resulted in greater inhibition of cell growth.
(3) Fenofibrate induced apoptosis of pancreatic cancer cells and treatment of fenofibrate plus gemcitabine potentiated the pro-apoptotic effects.
(4) Fenofibrate decreased the phosphorylation status of Akt and expression of survivin via up-regulation of TRB-3.
Part Two The Inhibitory Effect of Fenofibrate on Migration of Pancreatic Cancer Cells and Relevant Mechanisms
Objective:
We attempted to evaluate whether migration of pancreatic caner cells was affected by fenofibrate.
Materials and Methods:
(1) We used wound-healing assay to estimate the effect of fenofibrate on migration ability of pancreatic cancer cells.
(2) Cell migration was assessed quantitatively in Transwell chambers with polycarbonate filters.
(3) RT-PCR was used to determine the expression of E-cadherin and snail in pancreatic cancer cell lines incubated with different therapeutic modalities.
(4) Western blotting was done to detect E-cadherin,snail and phospho-GSK3βin pancreatic cancer cells after treatment with various agents.
Results:
(1) Wound gap was almost closed in control group after 24 hours wound introduction.In contrast,the speed of wound closure was much slower and the wounds were still widely open in the fenofibrate-treated group.
(2) Transwell chamber showed that the migration index in the presence of fenofibrate was 39.9±3.7%,significantly lower than the control group(P＜0.05). Gemcitabine did not cause significant decrease of migration index.
(3) RT-PCR results demonstrated that E-cadherin was up-regulated and snail was down-regulated after the fenofibrate treatment.The expression level of E-cadherin and snail was not affected by gemcitabine.
(4) Western blotting further confirmed that expression of E-cadherin increased and expression of snail decreased simultaneously in the fenofibrate-treated group.The protein levels of E-cadherin and snail remained similar after gemcitabine treatment compared with the control group.
(5) Down-regulation of phosphorylation status of GSK3βwas observed from the fenofibrate-treated group.
Conclusions:
(1) Fenofibrate inhibited migration of pancreatic cancer cells.
(2) Fenofibrate treatment led to impaired migration ability of pancreatic cancer cells via the attenuation of Akt/GSK3βmediated pathway.The decreased phosphorylation level of GSK3βrestored its kinase activity and subsequently blocked snail expression. Finally,the E-cadherin protein accumulated in pancreatic cancer cells treated with fenofibrate.
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