1、解螺旋陪伴医生科研成长 1 自噬与肿瘤细胞耐药自噬与肿瘤细胞耐药 本综述由解螺旋学员 旺 负责修订（2018 年 10 月）自噬（autophagy）是不同于凋亡的一种细胞死亡编程1-3。它是指胞质内双层膜包裹部分胞质和细胞内需降解的细胞器、蛋白质等成分形成自噬体（autophagosome），并与溶酶体融合形成自噬溶酶体，降解其所包裹内容物的过程4-6。自噬一方面为细胞本身代谢和某些细胞器更新提供能源；另一方面当细胞处于应激（如内质网应激、氧化应激和饥饿等）过剩状态时，细胞通过自噬方式“自杀”诱导细胞凋亡7。自噬的发生和发展和多种疾病都有联系，包括炎症、肿瘤和耐药8。解螺旋 研究发现，肿瘤细
2、胞在受到化疗药物刺激时，自噬信号通路被激活，自噬水平提高，从而分解这些药物分子，提高其自身对药物敏感性，促进细胞存活9。Juan Wang 等人研究发现激活 ERK/MAPK 信号可以提高自噬水平，从而加强卵巢癌细胞对顺铂的耐药性10;YANG X 等观察到缺氧诱导的自噬可以促进人膀胱癌细胞对吉西他滨的耐药11；相反，抑制自噬可以增加肿瘤细胞对化疗药物（如伊马替尼、紫杉醇、铂类药物和 5-氟尿嘧啶等）敏感性。体外实验表明乳腺癌细胞中凋亡关键因子的缺失和下调，以及自噬机制的激活可能是紫杉醇耐药的主要机制12，文献报道 p38 和 JNK/MAPK 通路在调控自噬和凋亡的平衡中起重要角色13。随着
3、研究不断进展，人们发现许多 microRNA（如 mir-155、miR-376b、miR-30a、miR-874）也可以通过抑制自噬加强癌细胞对化疗药物敏感性14-16。但是也有文献报道激活自噬会增强肿瘤细胞对药物的敏感性。Sirichanchuen 等人用顺铂和三氟拉嗪（自噬激活剂）同时处理肺癌耐药细胞株以后能够抑制肺癌耐药17。Zhou 课题组研究发现 mTOR 抑制剂和 Bacl-2 抑制剂可以通过激活乳腺癌细胞自噬方式增强乳腺癌对化疗药物敏感性，进一步证明自噬激活可以增强乳腺癌细胞药物敏感性18。解螺旋 细胞自噬在肿瘤细胞耐药过程中的作用具有两面性。自噬促进细胞生存还是死亡依赖于肿瘤
4、细胞的类型和不同的耐药性。在一些耐药的肿瘤细胞中可以检测到凋亡基因表达量减少，而在该情况下适应性自噬可以增加耐药细胞的耐药性；但在某些特定情况下，过度的自噬可以清除一些抗凋亡信号通路，反而增加耐药细胞对药物化疗的敏感性19。参考文献参考文献 1.Ren F,Shen J,Shi H,Hornicek FJ,Kan Q,Duan Z.Novel mechanisms and approaches to overcome multidrug resistance in the treatment of ovarian cancer.Biochim Biophys Acta 2016;1866(2)
5、:266-75.解螺旋陪伴医生科研成长 2 2.Moretti L,Yang ES,Kim KW,Lu B.Autophagy signaling in cancer and its potential as novel target to improve anticancer therapy.Drug resistance updates:reviews and commentaries in antimicrobial and anticancer chemotherapy 2007;10(4-5):135-43.3.Wang Y,Zhang N,Zhang L,et al.Autopha
6、gy Regulates Chromatin Ubiquitination in DNA Damage Response through Elimination of SQSTM1/p62.Mol Cell 2016;63(1):34-48.4.Haugen BR,Alexander EK,Bible KC,et al.2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer:The Ameri
7、can Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer.Thyroid 2016;26(1):1-133.解螺旋 5.Wei H,Wang C,Croce CM,Guan JL.p62/SQSTM1 synergizes with autophagy for tumor growth in vivo.Genes&development 2014;28(11):1204-16.6.Gao S,Sun D,Wang G,et al.Growth inhibi
8、tory effect of paratocarpin E,a prenylated chalcone isolated from Euphorbia humifusa Wild.,by induction of autophagy and apoptosis in human breast cancer cells.Bioorg Chem 2016;69:121-8.7.Jain K,Paranandi KS,Sridharan S,Basu A.Autophagy in breast cancer and its implications for therapy.Am J Cancer R
9、es 2013;3(3):251-65.8.Y B,F M,AM C.Autophagy and disease:always two sides to a problem.The Journal of pathology 2012;226(2):255-73.9.Guo XL,Li D,Hu F,et al.Targeting autophagy potentiates chemotherapy-induced apoptosis and proliferation inhibition in hepatocarcinoma cells.Cancer letters 2012;320(2):
10、171-9.10.Wang J,Wu GS.Role of autophagy in cisplatin resistance in ovarian cancer cells.The Journal of biological chemistry 2014;289(24):17163-73.11.H Y,Y Z,X L,et al.Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1 activation
11、.%A Yang X.Int J Oncol 2018;53(1):215-24.12.Ajabnoor GM,Crook T,Coley HM.Paclitaxel resistance is associated with switch from apoptotic to autophagic cell death in MCF-7 breast cancer cells.Cell death&disease 2012;3:e260.13.Sui X,Kong N,Ye L,et al.p38 and JNK MAPK pathways control the balance of apo
12、ptosis and autophagy in response to chemotherapeutic agents.Cancer letters 2014;344(2):174-9.14.Chen L,Jiang K,Jiang H,Wei P.miR155 mediates drug resistance in osteosarcoma cells via inducing autophagy.Experimental and Therapeutic Medicine 2014.15.Pan B,Yi J,Song H.MicroRNA-mediated autophagic signa
13、ling networks and cancer chemoresistance.Cancer biotherapy&radiopharmaceuticals 2013;28(8):573-8.16.J T,L Z,Y B,X Z.miR-874 regulates multiple-drug resistance in gastric cancer by targeting ATG16L1.Int J Oncol 2018;Epub ahead of print.17.Sirichanchuen B,Pengsuparp T,Chanvorachote P.Long-term cisplat
14、in exposure impairs autophagy and causes cisplatin resistance in human lung cancer cells.Molecular and cellular biochemistry 2012;364(1-2):11-8.18.Zhou S,Zhao L,Kuang M,et al.Autophagy in tumorigenesis and cancer therapy:Dr.Jekyll or Mr.Hyde?Cancer letters 2012;323(2):115-27.19.S H,E V,E B,VR W.The multifaceted role of autophagy in cancer and the microenvironment.Med Res Rev 2018;Epub ahead of print.
