Granato Marisa, Gilardini Montani Maria Saveria, Filardi Mariarosari, Faggioni Alberto, Cirone Mara
Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.
Oncotarget. 2015 Oct 6;6(30):29543-54. doi: 10.18632/oncotarget.4911.
Capsaicin, the pungent alkaloid of red pepper has been extensively studied for its many properties, especially the anti-inflammatory and anti-oxidant ones. It binds to vanilloid receptor 1, although it has been reported to be able to mediate some effects independently of its receptor. Another important property of Capsaicin is the anticancer activity against highly malignant tumors, alone or in combination with other chemotherapeutic agents. In this study, we found that Capsaicin induced an apoptotic cell death in PEL cells correlated with the inhibition of STAT3. STAT3 pathway, constitutively activated in PEL cells, is essential for their survival. By STAT3 de-phosphorylation, Capsaicin reduced the Mcl-1 expression level and this could represent one of the underlying mechanisms leading to the Capsaicin-mediated cell death and autophagy induction. Next, by pharmacological or genetic inhibition, we found that autophagy played a pro-survival role, suggesting that its inhibition could be exploited to increase the Capsaicin cytotoxic effect against PEL cells. Finally, we show that Capsaicin induced DAMP exposure, as for an immunogenic cell death, directly promoted DC activation and, more importantly, that it counteracted the immune-suppression, in terms of DC differentiation, mediated by the PEL released factors.
辣椒素是红辣椒中的辛辣生物碱，因其多种特性，尤其是抗炎和抗氧化特性，已得到广泛研究。它与香草酸受体1结合，不过据报道它能够独立于其受体介导一些效应。辣椒素的另一个重要特性是对高度恶性肿瘤具有抗癌活性，无论是单独使用还是与其他化疗药物联合使用。在本研究中，我们发现辣椒素诱导PEL细胞发生凋亡性细胞死亡，这与STAT3的抑制相关。STAT3通路在PEL细胞中持续激活，对其存活至关重要。通过使STAT3去磷酸化，辣椒素降低了Mcl-1表达水平，这可能是导致辣椒素介导的细胞死亡和自噬诱导的潜在机制之一。接下来，通过药理学或基因抑制，我们发现自噬发挥了促存活作用，这表明抑制自噬可用于增强辣椒素对PEL细胞的细胞毒性作用。最后，我们表明辣椒素诱导了DAMP暴露，如同免疫原性细胞死亡一样，直接促进了DC激活，更重要的是，它抵消了由PEL释放因子介导的DC分化方面的免疫抑制作用。
