Macropinocytosis: the big drinker behind cancer cell self-consumption
Macropinocytosis: the big drinker behind cancer cell self-consumption
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巨胞饮作用：癌细胞自我消耗背后的大饮酒者
DOI：
10.1080/15548627.2021.1919969
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发表时间：
2021
期刊：
影响因子：
13.3
通讯作者：
Michael Karin
中科院分区：
文献类型：
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作者：
Hua Su;Fei Yang;Beicheng Sun;Michael Karin
血管贫乏的肿瘤，如胰腺导管腺癌(PDAC)，嵌在厚厚的促结缔组织增生性间质中，营养紧张。这类肿瘤也是低氧的，依赖于许多适应性反应，包括巨噬/自噬和巨噬细胞增多(MP)，以支持它们的生物能量需求。自噬使饥饿的细胞能够通过溶酶体降解回收细胞内的大分子，并使用释放的氨基酸(AA)来为其新陈代谢提供燃料，而MP允许细胞通过液相内吞来摄取细胞外蛋白质，并将其用作能量来源。然而，任何MP激活的有机体，包括典型的癌细胞，是如何协调调节和平衡自噬和MP的，目前还不完全清楚。我们最近发现，抑制自噬导致MP上调，这使癌细胞能够克服自噬缺陷，并继续支持他们的生物能量需求。NFE2L2/NRF2驱动的MP相关基因(MRGs)的诱导负责自噬抑制、低氧和氧化应激暴露的癌细胞中MP的上调。同时自噬和MP阻断有效地切断了癌细胞的营养和供应，导致肿瘤迅速消退。这些发现表明MP是癌症治疗的重要靶点，切断能量龙头是一种有前景的治疗策略。缩写AA：氨基酸；ADC：自噬缺陷细胞；AI：自噬抑制；ALB：白蛋白；Chuk/ikkα：核因子kappa B激酶复合体的抑制成分；CQ：氯喹；ECM：细胞外基质；HCQ：羟基氯喹；MI：MP抑制；MP：巨噬细胞吞噬；MRGs：MP相关基因；MRPs：MP相关蛋白；PDAC：胰腺导管癌。
Poorly vascularized tumors embedded within a thick desmoplastic stroma, like pancreatic ductal adenocarcinoma (PDAC), are nutritionally stressed. Such tumors are also hypoxic and rely on a number of adaptive responses, including macroautophagy/autophagy and macropinocytosis (MP), to support their bioenergetic needs. Whereas autophagy enables starved cells to recycle intracellular macromolecules via lysosomal degradation and use the liberated amino acids (AA) to fuel their metabolism, MP allows cells to take up extracellular proteins via fluid-phase endocytosis and use them as an energy source. However, how any MP-enabled organism, including the prototypical cancer cell, coordinately regulates and balances autophagy and MP is not fully understood. We recently found that inhibition of autophagy results in upregulation of MP, which enables cancer cells to overcome autophagy deficiency and continue to support their bioenergetic demands. The NFE2L2/NRF2-driven induction of MP-related genes (MRGs) is responsible for the upregulation of MP in autophagy inhibited, hypoxic, and oxidatively stressed-exposed cancer cells. Concurrent autophagy and MP blockade effectively cuts off the cancer cell’s nutrient and supplies, leading to rapid tumor regression. These findings suggest MP to be an important target in cancer treatment and that shutting off the energy spigot is a promising therapeutic strategy.AbbreviationsAA: amino acids; ADCs: autophagy deficient-cells; AI: autophagy inhibition; ALB: albumin; CHUK/IKKα: component of inhibitor of nuclear factor kappa B kinase complex; CQ: chloroquine; ECM: extracellular matrix; HCQ: hydroxychloroquine; MI: MP inhibition; MP: macropinocytosis; MRGs: MP-related genes; MRPs: MP-related proteins; PDAC: pancreatic ductal adenocarcinoma.