Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, Hungary.
PLoS Genet. 2013;9(8):e1003664. doi: 10.1371/journal.pgen.1003664. Epub 2013 Aug 8.
Autophagy, a lysosomal self-degradation and recycling pathway, plays dual roles in tumorigenesis. Autophagy deficiency predisposes to cancer, at least in part, through accumulation of the selective autophagy cargo p62, leading to activation of antioxidant responses and tumor formation. While cell growth and autophagy are inversely regulated in most cells, elevated levels of autophagy are observed in many established tumors, presumably mediating survival of cancer cells. Still, the relationship of autophagy and oncogenic signaling is poorly characterized. Here we show that the evolutionarily conserved transcription factor Myc (dm), a proto-oncogene involved in cell growth and proliferation, is also a physiological regulator of autophagy in Drosophila melanogaster. Loss of Myc activity in null mutants or in somatic clones of cells inhibits autophagy. Forced expression of Myc results in cell-autonomous increases in cell growth, autophagy induction, and p62 (Ref2P)-mediated activation of Nrf2 (cnc), a transcription factor promoting antioxidant responses. Mechanistically, Myc overexpression increases unfolded protein response (UPR), which leads to PERK-dependent autophagy induction and may be responsible for p62 accumulation. Genetic or pharmacological inhibition of UPR, autophagy or p62/Nrf2 signaling prevents Myc-induced overgrowth, while these pathways are dispensable for proper growth of control cells. In addition, we show that the autophagy and antioxidant pathways are required in parallel for excess cell growth driven by Myc. Deregulated expression of Myc drives tumor progression in most human cancers, and UPR and autophagy have been implicated in the survival of Myc-dependent cancer cells. Our data obtained in a complete animal show that UPR, autophagy and p62/Nrf2 signaling are required for Myc-dependent cell growth. These novel results give additional support for finding future approaches to specifically inhibit the growth of cancer cells addicted to oncogenic Myc.
自噬是一种溶酶体自我降解和回收途径，在肿瘤发生中发挥双重作用。自噬缺陷至少部分地导致癌症易感性，这是由于选择性自噬货物 p62 的积累，导致抗氧化反应的激活和肿瘤形成。虽然大多数细胞中细胞生长和自噬是反向调节的，但在许多已建立的肿瘤中观察到自噬水平升高，推测介导癌细胞存活。然而，自噬与致癌信号之间的关系尚未得到充分表征。在这里，我们表明进化上保守的转录因子 Myc（dm），一种涉及细胞生长和增殖的原癌基因，也是果蝇中自噬的生理调节剂。在 null 突变体或细胞的体细胞克隆中丧失 Myc 活性会抑制自噬。Myc 的强制表达导致细胞自主的细胞生长增加、自噬诱导和 p62（Ref2P）介导的 Nrf2（cnc）激活，Nrf2 是促进抗氧化反应的转录因子。从机制上讲，Myc 过表达增加未折叠蛋白反应（UPR），导致 PERK 依赖性自噬诱导，可能是 p62 积累的原因。UPR、自噬或 p62/Nrf2 信号的遗传或药理学抑制可防止 Myc 诱导的过度生长，而这些途径对于对照细胞的正常生长是可有可无的。此外，我们表明，自噬和抗氧化途径在由 Myc 驱动的过量细胞生长中是平行需要的。Myc 的失调表达驱动大多数人类癌症的肿瘤进展，UPR 和自噬已被牵连到 Myc 依赖性癌细胞的存活中。我们在完整动物中获得的数据表明，UPR、自噬和 p62/Nrf2 信号对于 Myc 依赖性细胞生长是必需的。这些新的结果为寻找专门抑制依赖致癌 Myc 的癌细胞生长的未来方法提供了额外的支持。
