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Hexosamine pathway inhibition overcomes pancreatic cancer resistance to gemcitabine through unfolded protein response and EGFR-Akt pathway modulation.

氨基己糖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。

  • 影响因子:6.29
  • DOI:10.1038/s41388-020-1260-1
  • 作者列表:"Ricciardiello F","Gang Y","Palorini R","Li Q","Giampà M","Zhao F","You L","La Ferla B","De Vitto H","Guan W","Gu J","Zhang T","Zhao Y","Chiaradonna F
  • 发表时间:2020-03-31

: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.


: 不同的证据表明代谢重新布线是胰腺癌 (PC) 生长、侵袭和化疗耐药的必要条件。一个相关的作用已被分配到葡萄糖代谢。特别是,通过氨基己糖生物合成途径 (HBP) 的增强通量与 PC 发育紧密相关。在这里,我们表明通过磷酸乙酰氨基葡萄糖变位酶 3 (PGM3) 的上调,HBP 的增强与 PC 中吉西他滨 (GEM) 耐药的发生相关。事实上,GEM 敏感和耐药的患者来源肿瘤异种移植物 (PDXs) 的 mRNA 谱表明,在 GEM 耐药的 PDXs 中,PGM3 表达特异性增加。值得注意的是,与配对的癌旁正常组织相比,PGM3 结果在人 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。引人注目的是,遗传或药理学 PGM3 抑制可减少 PC 细胞生长、迁移、侵袭、体内肿瘤生长并增强 GEM 敏感性。因此,PGM3 的特异性抑制剂 (命名为 FR054) 和 GEM 之间的联合治疗导致异种移植肿瘤生长的有效减少,在正常组织中没有任何明显的副作用。机制上,PGM3 抑制,减少蛋白糖基化,引起持续的未折叠蛋白反应 (UPR),显著减弱致瘤性表皮生长因子受体 (EGFR)-Akt 轴,最后是细胞死亡。总之,本研究确定了 HBP 是参与 GEM 耐药的代谢途径,并为解决 PGM3 抑制剂和 GEM 联合治疗的 PC 疗法提供了强有力的理论基础。



作者列表:["Anuja K","Kar M","Chowdhury AR","Shankar G","Padhi S","Roy S","Akhter Y","Rath AK","Banerjee B"]

METHODS::Aims: Radiotherapy is predominantly used as one of the treatment modalities to treat local tumor in colorectal cancer (CRC). Hindrance in disease treatment can be attributed to radio-tolerance of cancer stem cells (CSCs) subsistence in the tumor. Understanding the radio-resistant property of CSCs might help in the accomplishment of targeted radiotherapy treatment and increased disease-free survival. Telomeric RAP1 contributes in modulation of various transcription factors leading to aberrant cell proliferation and tumor cell migration. Therefore, we investigated the role of RAP1 in maintaining resistance phenotype and acquired stemness in radio-resistant cells.Main Methods: Characterization of HCT116 derived radio-resistant cell (HCT116RR) was performed by cell survival and DNA damage profiling. RAP1 silenced cells were investigated for DNA damage and expression of CSC markers through western blotting and Real-time PCR post-irradiation. Molecular docking and co-immunoprecipitation study were performed to investigate RAP1 and KLF4 interaction followed by RAP1 protein status profiling in CRC patient.Key findings: We established radio-resistant cells, which showed tolerance to radiotherapy and elevated expression of CSC markers along with RAP1. RAP1 silencing showed enhanced DNA damage and reduced expression of CSC markers post-irradiation. We observed strong physical interaction between RAP1 and KLF4 protein. Furthermore, higher RAP1 expression was observed in the tumor of CRC patients. Dataset analysis also revealed that high expression of RAP1 expression is associated with poor prognosis.Significance: We conclude that higher expression ofRAP1 implicates its possible role in promoting radio-resistance in CRC cells by modulating DNA damage and CSC phenotype.

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作者列表:["Li Y","Wang Z","Jin J","Zhu SX","He GQ","Li SH","Wang J","Cai Y"]

METHODS::Cancer stem-like cells are rare immortal cells within tumor, which are thought to play important roles in ionizing radiation (IR) therapy-resistance. Quercetin is a natural flavonoid with potential anti-cancer properties without significant cytotoxicity in normal tissues. In this study, we demonstrated that quercetin-IR combination treatment exhibited more dramatic anti-cancer effect than either quercetin or IR treatment alone via targeting colon cancer stem cells (CSCs) and inhibiting the Notch-1 signaling. These effects were further verified by in vivo studies which showed remarkable decrease of the CSCs markers and the expression of Notch-1 signaling proteins in human colon cancer xenografts in nude mice. Co-treatment with quercetin and low dose of radiation significantly reduced the expressions of all five proteins of γ-secretase complex in HT-29 and DLD-1 cells. In addition, ectopic expression of the Notch intracellular domain (NICD) partly reversed the inhibition effects by the combination therapy. In conclusion, our results indicated that the combination of quercetin (20 μM) and IR (5Gy) might be a promising therapeutic strategy for colon cancer treatment by targeting colon cancer stem-like cells and inhibiting the Notch-1 signaling. In future studies, we intend to further explore the potential therapeutic efficacy of the quercetin-radiation combination treatment in clinical trials.

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作者列表:["Appelt AL","Andersen RF","Lindebjerg J","Jakobsen A"]

METHODS:OBJECTIVES:Long-term prevention of metastatic disease remains a challenge in locally advanced rectal cancer, and robust pretreatment prognostic factors for metastatic progression are lacking. We hypothesized that detecting circulating tumor-specific DNA (ctDNA) based on hypermethylation of the neuropeptide Y gene (meth-ctDNA) could be a prognostic marker in the neoadjuvant setting; we examined this in a secondary, explorative analysis of a prospective trial. MATERIALS AND METHODS:Serum samples were prospectively collected in a phase III trial for locally advanced rectal cancer. Positivity for and fractional abundance of meth-ctDNA in baseline samples were estimated. Overall survival (OS) and the rate of distant metastases were compared between meth-ctDNA positive and negative patients; other prognostic factors were controlled for in multivariate Cox regression. Importance of quantitative load was examined by considering the fractional abundance of meth-ctDNA relative to total circulating DNA. RESULTS:Baseline serum samples were available for 146 patients. In total, 30 patients had presence of meth-ctDNA, with no correlation with cT (P=0.8) or cN (P=0.6) stages. Median follow-up was 10.6 years for OS and 5.1 years for freedom from distant metastases. Patients with meth-ctDNA had significantly worse 5-year OS (47% vs. 69%), even when controlling for other prognostic factors (hazard ratio=2.08; 95% confidence interval, 1.23-1.51). This seemed mainly driven by disparity in the rate of distant metastases (55% vs. 72% at 5 y, P=0.01); hazard ratio=2.20 (95% confidence interval, 1.19-4.07, P=0.01) in multivariate analysis. Increased quantitative load was highly significant for worse outcomes. CONCLUSIONS:Meth-ctDNA could be a potential prognostic marker in the neoadjuvant setting and may, if validated, identify patients at increased risk of distant metastases.

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