Lin Chi-Iou, Whang Edward E, Abramson Michael A, Jiang Xiaofeng, Price Brendan D, Donner David B, Moore Francis D, Ruan Daniel T
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
Surgery. 2009 Dec;146(6):1208-14. doi: 10.1016/j.surg.2009.09.019.
Autophagy is a conserved response to stress that facilitates cell survival in some contexts and promotes cell death in others. We sought to characterize autophagy in papillary thyroid cancer (PTC), and to determine the effects of autophagy inhibition on chemosensitivity and radiosensitivity.
The human thyroid papillary carcinoma cell lines TPC-1 and 8505-C were treated with doxorubicin or radiation in the presence or absence of the autophagy-specific inhibitor 3-methyladenine (3-MA).
Although light chain 3 (LC3)-II protein levels were undetectable in normal thyroid and PTC specimens at baseline, doxorubicin exposure induced LC3-II expression and the formation of autophagosomes. Both PTC cell lines expressed low levels of LC3-II under standard conditions. Treatment of these cells with doxorubicin strongly induced LC3-II expression and the formation of autophagosomes; however, doxorubicin-mediated induction of LC3-II was abrogated by 3-MA. Moreover, 3-MA significantly increased the doxorubicin IC(50) in both PTC cell lines. Radiation exposure also induced LC3-II expression. Treatment with 3-MA abrogated the radiation-induced increase in LC3-II in both cell lines and reduced radiosensitivity by 49% and 31% in 8505-C and TPC-1 cells, respectively.
Autophagy inhibition promotes PTC resistance to doxorubicin and radiation. Therefore, autophagy activation may be a useful adjunct treatment for patients with PTC that is refractory to conventional therapy.
自噬是一种保守的应激反应，在某些情况下促进细胞存活，而在其他情况下促进细胞死亡。我们试图对甲状腺乳头状癌（PTC）中的自噬进行特征描述，并确定自噬抑制对化疗敏感性和放射敏感性的影响。
在存在或不存在自噬特异性抑制剂3-甲基腺嘌呤（3-MA）的情况下，用人甲状腺乳头状癌细胞系TPC-1和8505-C进行阿霉素或放射处理。
尽管在基线时正常甲状腺和PTC标本中未检测到轻链3（LC3）-II蛋白水平，但阿霉素暴露诱导了LC3-II表达和自噬体形成。在标准条件下，两种PTC细胞系均表达低水平的LC3-II。用阿霉素处理这些细胞强烈诱导了LC3-II表达和自噬体形成；然而，3-MA消除了阿霉素介导的LC3-II诱导。此外，3-MA显著增加了两种PTC细胞系中的阿霉素IC50。放射暴露也诱导了LC3-II表达。用3-MA处理消除了两种细胞系中放射诱导的LC3-II增加，并分别使8505-C和TPC-1细胞的放射敏感性降低了49%和31%。
自噬抑制促进PTC对阿霉素和放射的抗性。因此，自噬激活可能是对传统治疗难治的PTC患者的一种有用辅助治疗方法。
