Kim Sangmin, Jeon Myeongjin, Lee Jeong Eon, Nam Seok Jin
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 135-710, Republic of Korea.
Oncol Rep. 2016 Apr;35(4):2398-404. doi: 10.3892/or.2016.4557. Epub 2016 Jan 13.
Although tamoxifen reduces disease progression, tamoxifen resistance occurs during the course of estrogen receptor-positive [ER+] breast cancer treatment. In the present study, we investigated the possibility that interleukin-8 (IL-8) is a prognostic marker for tamoxifen resistance and aimed to clarify the regulation of IL-8 expression in tamoxifen-resistant cells. Clinically, IL-8 expression is positively correlated with survival in luminal A type breast cancer patients, but not in luminal B type breast cancer patients. In addition, the levels of IL-8 mRNA and protein expression were significantly increased in tamoxifen-resistant (TamR) cells compared to tamoxifen-sensitive (TamS) cells. To determine the regulatory mechanism of IL-8 expression in TamR cells, we analyzed the activities of signaling molecules. Our results showed that the phosphorylation levels of MEK and Akt were markedly increased in TamR cells, but there was no change in the phosphorylation level of p38 MAPK. On the contrary, we observed that elevated IL-8 mRNA expression was suppressed by a specific MEK1/2 inhibitor, UO126, but not by the specific PI-3K inhibitor LY294002, in TamR cells, whereas, we found that overexpression of constitutively active-MEK (CA-MEK) significantly increased the levels of IL-8 mRNA expression in TamS cells. Finally, we investigated the effect of the specific CXCR1/2 inhibitor SB225002 on anchorage-independent growth of TamR cells, and found that the growth was completely suppressed by SB225002. Taken together, our results demonstrate that IL-8 expression is regulated through a MEK/ERK-dependent pathway in TamR cells, suggesting that IL-8 and its receptors may be promising therapeutic targets for overcoming tamoxifen resistance.
尽管他莫昔芬可降低疾病进展，但在雌激素受体阳性[ER+]乳腺癌治疗过程中会出现他莫昔芬耐药。在本研究中，我们调查了白细胞介素-8（IL-8）作为他莫昔芬耐药预后标志物的可能性，并旨在阐明他莫昔芬耐药细胞中IL-8表达的调控机制。临床上，IL-8表达与腔面A型乳腺癌患者的生存率呈正相关，但与腔面B型乳腺癌患者无关。此外，与他莫昔芬敏感（TamS）细胞相比，他莫昔芬耐药（TamR）细胞中IL-8 mRNA和蛋白表达水平显著升高。为了确定TamR细胞中IL-8表达的调控机制，我们分析了信号分子的活性。我们的结果表明，TamR细胞中MEK和Akt的磷酸化水平显著升高，但p38 MAPK的磷酸化水平没有变化。相反，我们观察到，在TamR细胞中，特异性MEK1/2抑制剂UO126可抑制IL-8 mRNA表达的升高，但特异性PI-3K抑制剂LY294002则不能，而我们发现组成型活性MEK（CA-MEK）的过表达显著增加了TamS细胞中IL-8 mRNA的表达水平。最后，我们研究了特异性CXCR1/2抑制剂SB225002对TamR细胞非锚定依赖性生长的影响，发现SB225002可完全抑制其生长。综上所述，我们的结果表明，TamR细胞中IL-8的表达通过MEK/ERK依赖性途径调控，提示IL-8及其受体可能是克服他莫昔芬耐药的有前景的治疗靶点。
