国自然自噬与肿瘤细胞耐药

自噬与肿瘤细胞耐药自噬（autophagy）是不同于凋亡的一种细胞死亡编程i-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（au - to phagosome），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。研究表明，自噬过程与肿瘤细胞的发 生和发展有着密切关系，在肿瘤发展不同阶段，自噬所扮演角色也不同。目前一般认为在肿 瘤发生过程中，自噬抑制肿瘤的形成；在肿瘤发展阶段，促进肿瘤细胞存活，抑制凋亡，尤 其是在肿瘤对药物的应激上，对肿瘤耐药性的产生起着关键的调节作用8。研究发现，肿瘤细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,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11，文献报道p38和JNK/MAPK通路在调控自噬和凋亡的平衡中起重 要角色随着研究不断进展，人们发现许多microRNA（如mir-155、miR-376b、miR-30a） 也可以通过抑制自噬加强癌细胞对化疗药物敏感性13,14。但是也有文献报道激活自噬会降低 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 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提高乳腺癌对化疗药物敏感性，进一步证明自噬激活 可以降低乳腺癌细胞药物敏感性16。肿瘤细胞自噬在化疗过程中的作用可能与肿瘤类型及其 发展阶段、化疗药物种类、肿瘤细胞自身的承受能力有着密切关系。自噬是一把双刃剑，自 噬的水平决定着肿瘤细胞最终命运，温和而轻微的自噬可能会降低肿瘤细胞对化疗药物的敏 感性，相反地激烈或长时间的自噬可能会促进肿瘤细胞耐药。所以自噬对肿瘤细胞耐药性影 响的确切机制有待进一步研究。参考文献1. RenF,ShenJ,ShiH,HornicekFJ,KanQ,DuanZ.Novelmechanismsandapproaches to overcome multidrug resistance in the treatment of ovarian cancer. Biochimicaet biophysica acta2016; 1866(2): 266-75.2. Moretti L, Yang ES, Kim KW, Lu B. Autophagy signaling in cancer and its potentialas 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. Autophagy Regulates Chromatin Ubiquitination in DNA Damage Response through Elimination of SQSTM1/p62. Molecularcell 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 American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid : official journal of the American Thyroid Association2016; 26(1): 1-133.5. Wei H, Wang C, Croce CM, Guan JL. p62/SQSTM1 synergizes with autophagy for tumor growth in vivo. Genes & development2014; 28(11): 1204-16.6. Gao S, Sun D, Wang G, et al. Growth inhibitory effect of paratocarpin E, a prenylated chalcone isolated from Euphorbia humifusa Wild., by induction of autophagy and apoptosis in human breast cancer cells.Bioorganic chemistry2016; 69: 121-8.7. Jain K, Paranandi KS, Sridharan S, Basu A. Autophagy in breast cancer and its implications for therapy. American journal of cancer researc2h013; 3(3): 251-65.8. Yi H, Long B, Ye X, Zhang L, Liu X, Zhang C. Autophagy: A potential target for thyroid cancer therapy (Review). Molecularand clinicaloncology2014; 2(5): 661-5.9. 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): 171-9.10. Wang J, Wu GS. Role of autophagy in cisplatin resistance in ovarian cancer cells.The Journal of biological chemistr2y014; 289(24): 17163-73.11. 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: e260.12. Sui X, Kong N, Ye L, et al. p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents. Cancerletters2014; 344(2): 174-9.13. Chen L, Jiang K, Jiang H, Wei P. miR 155 mediates drug resistance in osteosarcoma cells via inducing autophagy. Experimental and Therapeutic Medicin2e014.14. Pan B, Yi J, Song H. MicroRNA-mediated autophagic signaling networks and cancer chemoresistance. Cancer biotherapy & radiopharmaceutical2s013; 28(8): 573-8.15. Sirichanchuen B, Pengsuparp T, Chanvorachote P. Long-term cisplatin exposure impairs autophagy and causes cisplatin resistance in human lung cancer cells. Molecular and cellular biochemistr2y012; 364(1-2): 11-8.16. Zhou S, Zhao L, Kuang M, et al. Autophagyin tumorigenesis and cancer therapy: Dr. Jekyll or Mr. Hyde? Cancer letters2012; 323(2): 115-27.