Hexosamine pathway inhibition overcomes pancreatic cancer resistance to gemcitabine through unfolded protein response and EGFR-Akt pathway modulation
Hexosamine pathway inhibition overcomes pancreatic cancer resistance to gemcitabine through unfolded protein response and EGFR-Akt pathway modulation
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己糖胺通路抑制通过未折叠蛋白反应和 EGFR-Akt 通路调节克服胰腺癌对吉西他滨的耐药性
DOI：
10.1038/s41388-020-1260-1
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发表时间：
2020-03-31
期刊：
影响因子：
8
通讯作者：
Chiaradonna, Ferdinando
中科院分区：
文献类型：
--
作者：
Ricciardiello, Francesca;Gang, Yang;Chiaradonna, Ferdinando
不同的证据表明，代谢重排是胰腺癌(PC)生长、侵袭和化疗耐药的必要条件。葡萄糖代谢也被赋予了相关的角色。特别是，通过己糖胺生物合成途径(HBP)的增强通量与PC开发密切相关。在这里，我们表明，通过上调磷酸乙酰氨基葡萄糖变位酶3(PGM3)，HBP的增强与PC对吉西他滨(GEM)耐药的发生有关。事实上，对GEM敏感和耐药的患者来源的肿瘤异种移植(PDX)的mRNA图谱表明，PGM3在GEM耐药的PDX中的表达特异性增加。值得注意的是，与配对的邻近正常组织相比，PGM3在人PC组织中也过表达，其在PC患者中的高表达与较差的中位总生存期(OS)相关。值得注意的是，基因或药物上的PGM3抑制可减少PC细胞的生长、迁移、侵袭，体内肿瘤生长，并增强GEM的敏感性。因此，在正常组织中，名为FR054的PGM3特异性抑制剂和GEM之间的联合治疗可以有效地减少异种移植瘤的生长，而没有任何明显的副作用。从机制上讲，抑制PGM3，减少蛋白质糖基化，导致持续的未折叠蛋白质反应(UPR)，使促肿瘤的表皮生长因子受体(EGFR)-Akt轴显著减弱，最终导致细胞死亡。总之，这项研究确定HBP是参与GEM耐药的代谢途径，并为PC治疗与PGM3抑制剂和GEM的联合治疗提供了强有力的理论基础。
Different evidence has indicated metabolic rewiring as a necessity for pancreatic cancer (PC) growth, invasion, and chemotherapy resistance. A relevant role has been assigned to glucose metabolism. In particular, an enhanced flux through the Hexosamine Biosynthetic Pathway (HBP) has been tightly linked to PC development. Here, we show that enhancement of the HBP, through the upregulation of the enzyme Phosphoacetylglucosamine Mutase 3 (PGM3), is associated with the onset of gemcitabine (GEM) resistance in PC. Indeed, mRNA profiles of GEM sensitive and resistant patient-derived tumor xenografts (PDXs) indicate that PGM3 expression is specifically increased in GEM-resistant PDXs. Of note, PGM3 results also overexpressed in human PC tissues as compared to paired adjacent normal tissues and its higher expression in PC patients is associated with worse median overall survival (OS). Strikingly, genetic or pharmacological PGM3 inhibition reduces PC cell growth, migration, invasion, in vivo tumor growth and enhances GEM sensitivity. Thus, combined treatment between a specific inhibitor of PGM3, named FR054, and GEM results in a potent reduction of xenograft tumor growth without any obvious side effects in normal tissues. Mechanistically, PGM3 inhibition, reducing protein glycosylation, causes a sustained Unfolded Protein Response (UPR), a significant attenuation of the pro-tumorigenic Epidermal Growth Factor Receptor (EGFR)-Akt axis, and finally cell death. In conclusion this study identifies the HBP as a metabolic pathway involved in GEM resistance and provides a strong rationale for a PC therapy addressing the combined treatment with the PGM3 inhibitor and GEM.