Department of Ecological and Biological Sciences, Tuscia University, Largo dell'Università, Blocco C, 01100 Viterbo, Italy.
Cancer Immunol Immunother. 2011 Oct;60(10):1503-7. doi: 10.1007/s00262-011-1074-7. Epub 2011 Jul 22.
Some anticancer chemotherapeutics, such as anthracyclines and oxaliplatin, elicit immunogenic apoptosis, meaning that dying cancer cells are engulfed by dendritic cells and tumor antigens are efficiently presented to CD8+ T cells, which control residual tumor cells. Immunogenic apoptosis is characterized by pre-apoptotic cell surface exposure of calreticulin (CRT), which usually resides into the endoplasmic reticulum. We investigated the ability of the n3-polyunsaturated fatty acid docosahexaenoic acid (22:6n3, DHA) to induce pre-apoptotic CRT exposure on the surface of the human PaCa-44 pancreatic and EJ bladder cancer cell lines. Cells were treated with 150 μM DHA for different time periods, and, by immunoblot and immunofluorescence, we showed that DHA induced CRT exposure, before the apoptosis-associated phosphatidylserine exposure. As for the known immunogenic compounds, CRT exposure was inhibited by the antioxidant GSH, the pan-caspase zVAD-FMK, and caspase-8 IETD-FMK inhibitor. We provide the first evidence that DHA induces CRT exposure, representing thus a novel potential anticancer immunogenic chemotherapeutic agent.
一些抗癌化疗药物，如蒽环类药物和奥沙利铂，会引发免疫原性细胞凋亡，即垂死的癌细胞被树突状细胞吞噬，肿瘤抗原被有效地呈递给 CD8+T 细胞，从而控制残留的肿瘤细胞。免疫原性细胞凋亡的特征是细胞表面预先凋亡时钙网蛋白（CRT）的暴露，而 CRT 通常位于内质网中。我们研究了 n3 多不饱和脂肪酸二十二碳六烯酸（22:6n3，DHA）诱导人胰腺癌细胞系 PaCa-44 和膀胱癌细胞系 EJ 表面预先凋亡 CRT 暴露的能力。用 150μM DHA 处理细胞不同时间后，通过免疫印迹和免疫荧光，我们发现 DHA 在与凋亡相关的磷脂酰丝氨酸暴露之前诱导 CRT 暴露。与已知的免疫原性化合物一样，CRT 暴露被抗氧化剂 GSH、广谱半胱天冬酶抑制剂 zVAD-FMK 和半胱天冬酶-8 IETD-FMK 抑制剂所抑制。我们提供了第一个证据表明 DHA 诱导 CRT 暴露，这代表了一种新的潜在的抗癌免疫化疗药物。
