Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer.
Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer.
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DOI：
10.4161/auto.6.3.11625
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发表时间：
2010-04
期刊：
影响因子：
13.3
通讯作者：
Ozpolat B
中科院分区：
文献类型：
--
作者：
Dalby KN;Tekedereli I;Lopez-Berestein G;Ozpolat B
自噬是一种进化上保守的降解细胞质蛋白、大分子和细胞器的溶酶体途径。虽然自噬已成为癌症研究中最具吸引力的话题之一，但目前的自噬文献往往被认为是令人困惑的，因为它与生存和细胞死亡等明显矛盾的角色有关。自噬可以作为肿瘤抑制因子，自噬能力的部分降低或自噬缺陷（如小鼠杂合敲低BECN1(+/−)）提供致癌刺激，引起恶性转化和自发肿瘤。此外，自噬似乎是一种保护细胞生存的机制，可以抵抗环境和细胞应激（如营养剥夺、缺氧和治疗应激），并引起对抗肿瘤治疗的抵抗。最近的研究表明，抑制癌细胞的自噬在某些情况下可能在治疗上有益，因为它可以使癌细胞对不同的治疗方法敏感，包括dna损伤剂、抗激素治疗（如他莫昔芬）和放射治疗。这支持了抑制自噬可以负面影响癌细胞存活并增加细胞死亡的假设，当与抗癌药物联合使用时，提供了治疗癌症的优势。另一方面，通过抑制抗自噬蛋白如Bcl-2、PKCδ和组织转谷氨酰胺酶2 （TG2）来诱导自噬，可能导致一些凋亡抵抗性癌症（如乳腺癌和胰腺癌）的自噬细胞死亡，这表明单独诱导自噬也可能被用作一种潜在的治疗方法。总的来说，数据表明，根据细胞特征，诱导或抑制自噬可以为患者提供治疗益处，第一代自噬调节剂的设计和合成可能为概念实验的证明提供工具，并为最终可能导致新的癌症治疗策略的转化研究提供动力。
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, PKCδ, 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.
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