哇巴因特异性调节细胞生长与Na~+/K~+-ATP酶表达的关系
摘要
本实验研究发现，哇巴因能够特异性地调节细胞生长，同时也特异性地调节细胞钠钾ATP酶的表达。减少细胞钠钾ATP酶可以减慢细胞的增殖，也可以转化哇巴因对细胞生长的促进作用变为抑制作用。用相同的实验条件作用于猪肾近曲小管上皮细胞株(LLC-PK1)、人乳腺癌细胞株(BT20)和前列腺癌细胞株(DU145)后，两种肿瘤细胞株的钠钾ATP酶细胞量减少，而猪肾近曲小管上皮细胞株(LLC-PK1)的钠钾ATP酶反而增加。用实时荧光定量PCR(Real-Time PCR)方法研究哇巴因对钠钾ATP酶的转录是否有影响，根据实验结果可以判断，哇巴因对钠钾ATP酶的调节不是通过转录水平，哇巴因不影响mRNA的量。前期实验已经证实，mTOR可以增加许多种mRNAs的翻译，通过实验我们发现哇巴因作用于钠钾ATP酶受体后，本质上是通过对PI3K／Akt／mTOR信号通路的调节改变了钠钾ATP酶的细胞量，从而达到调节细胞生长的作用。将哇巴因作用于猪肾近曲小管上皮细胞株(LLC-PK1)、人乳腺癌细胞株(BT20)和前列腺癌细胞株(DU145)后，通过和钠钾ATP酶受体的结合，刺激钠钾ATP酶的内吞作用，同时加速了酶的降解。但是，对于猪肾近曲小管上皮细胞株，哇巴因同时可以通过刺激PI3K／Akt／mTOR信号通路增加钠钾ATP酶的表达，最终钠钾ATP酶的细胞总量不变或者增加从而刺激细胞的生长。哇巴因并未刺激人乳腺癌细胞(BT20)和前列腺癌细胞(DU145)钠钾ATP酶的表达。不仅如此，PI3K／Akt／mTOR信号通路的抑制药物雷帕霉素(rapamycin)不仅完全阻断了哇巴因对猪肾近曲小管上皮细胞生长的促进作用，而且还将促进作用转变为抑制作用。
另一方面，有文献报道哇巴因抑制乳腺癌细胞株MDA-MB-435s的生长是通过刺激细胞周期抑制因子p21~(cip)表达所起的作用。根据实验结果我们观察到，在人乳腺癌细胞株和前列腺癌细胞株的试验中，哇巴因导致细胞中钠钾ATP酶减少并且刺激了细胞周期抑制因子p21~(cip)的表达，最终抑制细胞的生长。其它实验同样可以观察到一致的实验结果。通过RNA干扰技术减少细胞钠钾ATP酶的量，酶的减少不仅诱导细胞周期抑制因子p21~(cip)的表达而且抑制了细胞的生长。另外，即便作用于猪肾近曲小管上皮细胞，通过实验手段减少细胞钠钾ATP酶的量也可以将哇巴因对细胞生长的促进作用转变为抑制作用。
前期研究发现钠钾ATP酶是通过在caveolae和Src形成复杂的受体发挥它的信号传导功能。理论上，Src和caveolin-1是哇巴因激活Akt以及上调细胞钠钾ATP酶表达的两个重要影响因子。正如预测，缺乏Src时哇巴因不能促进αl的表达。通过恢复细胞内Src，也可以恢复哇巴因上调αl表达的生物学作用。同样地，减少caveolin-1的表达，哇巴因不能再刺激αl的合成，在这些细胞中，也不能激活Akt。此外，减少caveolin-1的表达，哇巴因不仅无法上调α1，促进细胞的生长；相反，哇巴因可以抑制细胞的增殖。
总之，通过实验得出结论，根据钠钾ATP酶表达的变化可以判断哇巴因对细胞生长的调节作用，而钠钟ATP酶可能成为癌症治疗的新靶点。
In this thesis,we used kidney epithelial cells (LLC-PK1).breast cancer cells(BT20) and prostate cancer cells (DU145) to compare the cell growth andNa/K-ATPase expression levels.The results showed that ouabain differentiallyregulates cell growth in these three cell lines.It stimulated LLC-PK1 cellsproliferation at 10 to 50 nM,but induced cell growth inhibition at the sameconcentrations in BT20 cells and DU145 cells.Meanwhile,treatment with lowconcentration of ouabain up-regulated the Na/K-ATPase expression in LLC-PK1cells but dramatically decreased Na/K-ATPase amount in BT20 cells and DU145cells.Collectively,we show that ouabain-induced cell growth regulation isintrinsically coupled to changes in the cellular amount of Na~+/K~+-ATPase via thePI3K/Akt/mTOR pathway.Ouabain increases the endocytosis and degradation ofNa~+/K~+-ATPase in LLC-PK1,human breast (BT20) and prostate (DU145) cancercells.However,ouabain stimulates the PI3K/Akt/mTOR pathway andconsequently up-regulates the expression of Na~+/K~+-ATPase in LLC-PK1,but notBT20 and DU145 cells.This up-regulation is sufficient to replete the plasmamembrane pool of Na~+/K~+-ATPase and stimulate cell growth in LLC-pK1 cells.Onthe other hand,ouabain causes a gradual depletion of Na~+/K~+-ATPase,andconsequently an increased expression of cell cycle inhibitor p21~(cip) and cell growthinhibition in BT20 and DU 145 cells.Consistently,we observe that siRNA-mediated knockdown of Na~+/K~+-ATPase is sufficient to induce the expression of p21~(cip) andslow the growth of LLC-PK1 cells.Moreover,this knockdown converts thegrowth stimulatory effect of ouabain to growth inhibition in LLC-PK1 cells.Mechanistically,both Src and caveolin-1 are required for ouabain-inducedactivation of Akt and up-regulation of Na~+/K~+-ATPase.Furthermore,inhibition ofthe PI3K/Akt/mTOR pathway by rapamycin completely blocks ouabain-inducedexpression of Na~+/K~+-ATPase,and converts ouabain-induced growth stimulation togrowth inhibition in LLC-PK1 cells.Taken together,we conclude that changes inthe expression of Na~+/K~+-ATPase dictate the growth regulatory effects of ouabainon cells.We also suggest that the expression of Na~+/K~+-ATPase may be targeted fordeveloping new anti-cancer therapeutics.
另一方面，有文献报道哇巴因抑制乳腺癌细胞株MDA-MB-435s的生长是通过刺激细胞周期抑制因子p21~(cip)表达所起的作用。根据实验结果我们观察到，在人乳腺癌细胞株和前列腺癌细胞株的试验中，哇巴因导致细胞中钠钾ATP酶减少并且刺激了细胞周期抑制因子p21~(cip)的表达，最终抑制细胞的生长。其它实验同样可以观察到一致的实验结果。通过RNA干扰技术减少细胞钠钾ATP酶的量，酶的减少不仅诱导细胞周期抑制因子p21~(cip)的表达而且抑制了细胞的生长。另外，即便作用于猪肾近曲小管上皮细胞，通过实验手段减少细胞钠钾ATP酶的量也可以将哇巴因对细胞生长的促进作用转变为抑制作用。
前期研究发现钠钾ATP酶是通过在caveolae和Src形成复杂的受体发挥它的信号传导功能。理论上，Src和caveolin-1是哇巴因激活Akt以及上调细胞钠钾ATP酶表达的两个重要影响因子。正如预测，缺乏Src时哇巴因不能促进αl的表达。通过恢复细胞内Src，也可以恢复哇巴因上调αl表达的生物学作用。同样地，减少caveolin-1的表达，哇巴因不能再刺激αl的合成，在这些细胞中，也不能激活Akt。此外，减少caveolin-1的表达，哇巴因不仅无法上调α1，促进细胞的生长；相反，哇巴因可以抑制细胞的增殖。
总之，通过实验得出结论，根据钠钾ATP酶表达的变化可以判断哇巴因对细胞生长的调节作用，而钠钟ATP酶可能成为癌症治疗的新靶点。
In this thesis,we used kidney epithelial cells (LLC-PK1).breast cancer cells(BT20) and prostate cancer cells (DU145) to compare the cell growth andNa/K-ATPase expression levels.The results showed that ouabain differentiallyregulates cell growth in these three cell lines.It stimulated LLC-PK1 cellsproliferation at 10 to 50 nM,but induced cell growth inhibition at the sameconcentrations in BT20 cells and DU145 cells.Meanwhile,treatment with lowconcentration of ouabain up-regulated the Na/K-ATPase expression in LLC-PK1cells but dramatically decreased Na/K-ATPase amount in BT20 cells and DU145cells.Collectively,we show that ouabain-induced cell growth regulation isintrinsically coupled to changes in the cellular amount of Na~+/K~+-ATPase via thePI3K/Akt/mTOR pathway.Ouabain increases the endocytosis and degradation ofNa~+/K~+-ATPase in LLC-PK1,human breast (BT20) and prostate (DU145) cancercells.However,ouabain stimulates the PI3K/Akt/mTOR pathway andconsequently up-regulates the expression of Na~+/K~+-ATPase in LLC-PK1,but notBT20 and DU145 cells.This up-regulation is sufficient to replete the plasmamembrane pool of Na~+/K~+-ATPase and stimulate cell growth in LLC-pK1 cells.Onthe other hand,ouabain causes a gradual depletion of Na~+/K~+-ATPase,andconsequently an increased expression of cell cycle inhibitor p21~(cip) and cell growthinhibition in BT20 and DU 145 cells.Consistently,we observe that siRNA-mediated knockdown of Na~+/K~+-ATPase is sufficient to induce the expression of p21~(cip) andslow the growth of LLC-PK1 cells.Moreover,this knockdown converts thegrowth stimulatory effect of ouabain to growth inhibition in LLC-PK1 cells.Mechanistically,both Src and caveolin-1 are required for ouabain-inducedactivation of Akt and up-regulation of Na~+/K~+-ATPase.Furthermore,inhibition ofthe PI3K/Akt/mTOR pathway by rapamycin completely blocks ouabain-inducedexpression of Na~+/K~+-ATPase,and converts ouabain-induced growth stimulation togrowth inhibition in LLC-PK1 cells.Taken together,we conclude that changes inthe expression of Na~+/K~+-ATPase dictate the growth regulatory effects of ouabainon cells.We also suggest that the expression of Na~+/K~+-ATPase may be targeted fordeveloping new anti-cancer therapeutics.
引文
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