Depletion of intrinsic expression of Interleukin-8 in prostate cancer cells causes cell cycle arrest, spontaneous apoptosis and increases the efficacy of chemotherapeutic drugs.
Depletion of intrinsic expression of Interleukin-8 in prostate cancer cells causes cell cycle arrest, spontaneous apoptosis and increases the efficacy of chemotherapeutic drugs.
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DOI：
10.1186/1476-4598-8-57
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发表时间：
2009-07-31
期刊：
影响因子：
37.3
通讯作者：
Lokeshwar BL
中科院分区：
文献类型：
--
作者：
Singh RK;Lokeshwar BL
所有癌症的发展都以细胞增殖增加和细胞凋亡减少为特征。雄激素非依赖性前列腺癌(AIPC)是疾病的终末期。许多趋化因子和细胞因子可能导致肿瘤细胞存活率增加，最终导致对治疗的抵抗和宿主的死亡。AIPC细胞，而不是雄激素反应细胞，结构性地表达大量的促炎趋化因子，白介素8(IL-8)。IL-8介导的AIPC细胞存活和耐药机制目前尚不清楚。本报告的目的是展示IL-8在雄激素非依赖性前列腺癌(AIPC)恶性进展中的普遍作用，并利用RNA干扰提供一种潜在的新的治疗途径。通过对两个分泌IL-8的AIPC细胞系PC-3和DU145进行RNA干扰，研究了IL-8缺失对AIPC细胞功能的影响。以不分泌IL-8的LNCaP细胞和LAPC-4细胞为对照。用不含RISC的siRNA(对照)或验证过的IL-8 siRNA池转染细胞。50 nM的IL-8 siRNA可使IL-8基因表达减少95%，IL-8蛋白表达减少92%。IL-8的这种降低导致细胞周期停滞在G1/S交界处，细胞周期调节蛋白Cyclin D1和Cyclin B1减少(均下降50%)，并抑制ERK1/2活性50%。此外，在IL-8耗竭的细胞中，自发凋亡增加了43%，caspase-9的激活和裂解的PARP的增加证明了这一点。IL-8的缺失导致抗凋亡蛋白、bcl2、bclxl的表达显著降低，其原因是mRNA和翻译后稳定性降低，而促凋亡的bax和BAD蛋白水平升高。更重要的是，细胞内IL-8的耗尽增加了多种化疗药物的细胞毒活性。与C-siRNA转染组相比，多西紫杉醇、司他诺孢菌素和雷帕霉素对IL-8耗竭细胞的细胞毒作用显著增强(IC50为40%)。这些结果表明，无论抗增殖药物的细胞毒性机制如何，IL-8在促进肿瘤细胞存活和抵抗细胞毒药物方面的普遍作用，并指出了IL-8缺失在男性AIPC中的潜在治疗意义。
The progression of all cancers is characterized by increased-cell proliferation and decreased-apoptosis. The androgen-independent prostate cancer (AIPC) is the terminal stage of the disease. Many chemokines and cytokines are suspects to cause this increased tumor cell survival that ultimately leads to resistance to therapy and demise of the host. The AIPC cells, but not androgen-responsive cells, constitutively express abundant amount of the pro-inflammatory chemokine, Interleukin-8 (IL-8). The mechanism of IL-8 mediated survival and therapeutic resistance in AIPC cells is unclear at present. The purpose of this report is to show the pervasive role of IL-8 in malignant progression of androgen-independent prostate cancer (AIPC) and to provide a potential new therapeutic avenue, using RNA interference. The functional consequence of IL-8 depletion in AIPC cells was investigated by RNA interference in two IL-8 secreting AIPC cell lines, PC-3 and DU145. The non-IL-8 secreting LNCaP and LAPC-4 cells served as controls. Cells were transfected with RISC-free siRNA (control) or validated-pool of IL-8 siRNA. Transfection with 50 nM IL-8 siRNA caused >95% depletion of IL-8 mRNA and >92% decrease in IL-8 protein. This reduction in IL-8 led to cell cycle arrest at G1/S boundary and decreases in cell cycle-regulated proteins: Cyclin D1 and Cyclin B1 (both decreased >50%) and inhibition of ERK1/2 activity by >50%. Further, the spontaneous apoptosis was increased by >43% in IL-8 depleted cells, evidenced by increases in caspase-9 activation and cleaved-PARP. IL-8 depletion caused significant decreases in anti-apoptotic proteins, BCL-2, BCL-xL due to decrease in both mRNA and post-translational stability, and increased levels of pro-apoptotic BAX and BAD proteins. More significantly, depletion of intracellular IL-8 increased the cytotoxic activity of multiple chemotherapeutic drugs. Specifically, the cytotoxicity of Docetaxel, Staurosporine and Rapamycin increased significantly (>40% at IC50 dose) in IL-8 depleted cells as compared to that in C-siRNA transfected cells. These results show the pervasive role of IL-8 in promoting tumor cell survival, and resistance to cytotoxic drugs, regardless of the cytotoxic mechanism of antiproliferative drugs, and point to potential therapeutic significance of IL-8 depletion in men with AIPC.
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DOI：
10.1158/1078-0432.ccr-08-0738
发表时间：
2008-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Caruso DJ;Carmack AJ;Lokeshwar VB;Duncan RC;Soloway MS;Lokeshwar BL
通讯作者：
Lokeshwar BL
DOI：
10.1016/j.urolonc.2007.05.010
发表时间：
2007-09-01
影响因子：
2.7
作者：
Hadaschik, Boris A.;Gleave, Martin E.
通讯作者：
Gleave, Martin E.
影响因子：
11.5
作者：
Dandekar, DS;Lokeshwar, BL
通讯作者：
Lokeshwar, BL
影响因子：
3.6
作者：
Chavey, Carine;Muehlbauer, Marcus;Lazennec, Gwendal
通讯作者：
Lazennec, Gwendal
影响因子：
56.9
作者：
HOLMES, WE;LEE, J;WOOD, WI
通讯作者：
WOOD, WI