Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.
Autophagy. 2010 Apr;6(3):322-9. doi: 10.4161/auto.6.3.11625. Epub 2010 Apr 26.
Autophagy is an evolutionarily conserved lysosomal pathway for degrading cytoplasmic proteins, macromolecules, and organelles. While autophagy has become one of the most attractive topics in cancer research, the current autophagy literature is often viewed as confusing, because of its association with apparently contradictory roles, such as survival and cell death. Autophagy can serve as a tumor suppressor, as a partial reduction in autophagic capacity or defective autophagy (e.g., heterozygous knockdown BECN1 (+/-) in mice) provides an oncogenic stimulus, causing malignant transformation and spontaneous tumors. In addition, autophagy seems to function as a protective cell survival mechanism against environmental and cellular stress (e.g., nutrient deprivation, hypoxia and therapeutic stress) and causes resistance to antineoplastic therapies. Recent studies have demonstrated that the inhibition of autophagy in cancer cells may be therapeutically beneficial in some circumstances, as it can sensitize cancer cells to different therapies, including DNA-damaging agents, antihormone therapies (e.g., tamoxifen), and radiation therapy. This supports the hypothesis that inhibiting autophagy can negatively influence cancer cell survival and increase cell death when combined with anticancer agents, providing a therapeutic advantage against cancer. On the other hand, the induction of autophagy by the inhibition of anti-autophagic proteins, such as Bcl-2, PKCdelta, and tissue transglutaminase 2 (TG2), may lead to autophagic cell death in some apoptosis-resistant cancers (i.e., breast and pancreatic cancers), indicating that the induction of autophagy alone may also be used as a potential therapy. Overall, the data suggest that, depending on the cellular features, either the induction or the inhibition of autophagy can provide therapeutic benefits to patients and that the design and synthesis of the first-generation modulators of autophagy may provide the tools for proof of concept experiments and the impetus for translational studies that may ultimately lead to new therapeutic strategies in cancer.
自噬是一种进化上保守的溶酶体途径，用于降解细胞质蛋白、大分子和细胞器。虽然自噬已成为癌症研究中最具吸引力的课题之一，但由于其与明显矛盾的作用（如生存和细胞死亡）有关，当前的自噬文献往往被认为令人困惑。自噬可以作为肿瘤抑制因子，因为自噬能力的部分降低或缺陷的自噬（例如，小鼠中 BECN1 杂合敲低（+/−））提供了致癌刺激，导致恶性转化和自发性肿瘤。此外，自噬似乎作为一种针对环境和细胞应激（例如，营养剥夺、缺氧和治疗性应激）的保护性细胞存活机制发挥作用，并导致对抗肿瘤治疗的耐药性。最近的研究表明，在某些情况下，抑制癌细胞中的自噬可能具有治疗益处，因为它可以使癌细胞对不同的治疗方法（包括 DNA 损伤剂、抗激素治疗（例如，他莫昔芬）和放射治疗）敏感。这支持了这样一种假设，即抑制自噬可以在与抗癌药物联合使用时对癌细胞的存活产生负面影响并增加细胞死亡，从而为癌症提供治疗优势。另一方面，通过抑制抗自噬蛋白（如 Bcl-2、PKCdelta 和组织转谷氨酰胺酶 2（TG2））诱导自噬可能导致一些抗凋亡癌症（即乳腺癌和胰腺癌）中的自噬细胞死亡，表明单独诱导自噬也可能被用作一种潜在的治疗方法。总体而言，数据表明，根据细胞特征，诱导或抑制自噬都可以为患者提供治疗益处，并且自噬的第一代调节剂的设计和合成可能为概念验证实验提供工具，并为转化研究提供动力，最终可能导致癌症的新治疗策略。
