Department of and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine Atlanta, GA, USA.
Autophagy. 2011 Apr;7(4):448-9. doi: 10.4161/auto.7.4.14683. Epub 2011 Apr 1.
The increasing appreciation of the importance of autophagy as consequence of cancer therapy or underlying disease biology is illustrated by the large number of papers that are evaluating autophagy as a cancer target. While autophagy is often linked to the generation of metabolic precursors, it is also important in diseases where protein production is a hallmark of the disease itself, such as pancreatic cancer and multiple myeloma. Multiple myeloma is characterized by ongoing autophagy as a consequence of constitutive immunoglobulin production, which creates the need for efficient transfer and disposal of misfolded or unfolded proteins. In order to survive this cellular stress, plasma cells depend on proteasomal degradation of the large volume of misfolded proteins as well as the autophagy pathway. It has previously been suggested that the excess proteins not targeted to the proteasome, or that accumulate when the proteasome is inhibited through the use of chemically active agents such as bortezomib, are linked to impaired cell survival, and that their packaging in the form of an aggresome somehow minimizes their 'proteotoxicity' allowing these toxic proteins to be sequestered away from normal cellular machinery.
越来越多的人认识到自噬在癌症治疗或潜在疾病生物学中的重要性，这体现在大量评估自噬作为癌症靶点的论文上。虽然自噬通常与代谢前体的产生有关，但在某些疾病中，蛋白质的产生本身就是疾病的标志，如胰腺癌和多发性骨髓瘤。多发性骨髓瘤的特点是由于持续的免疫球蛋白产生而导致持续的自噬，这就需要有效地转移和处理错误折叠或未折叠的蛋白质。为了应对这种细胞应激，浆细胞依赖于蛋白酶体降解大量错误折叠的蛋白质以及自噬途径。先前有研究表明，过量的未靶向蛋白酶体的蛋白质，或者当蛋白酶体被化学活性药物（如硼替佐米）抑制时积累的蛋白质，与细胞存活受损有关，它们以聚集体的形式包装，以某种方式最小化其“蛋白毒性”，从而使这些有毒蛋白质与正常细胞机制隔离。
