ABHD5 blunts the sensitivity of colorectal cancer to fluorouracil via promoting autophagic uracil yield
ABHD5 blunts the sensitivity of colorectal cancer to fluorouracil via promoting autophagic uracil yield
复制标题
ABHD5 通过促进自噬尿嘧啶产量降低结直肠癌对氟尿嘧啶的敏感性
DOI：
10.1038/s41467-019-08902-x
复制
发表时间：
2019-03-06
影响因子：
16.6
通讯作者：
Liang，Houjie
中科院分区：
文献类型：
--
作者：
Ou，Juanjuan;Peng，Yuan;Liang，Houjie
氟尿嘧啶（FU）治疗结直肠癌（CRC）的疗效受到耐药性的极大限制。自噬与化疗耐药性有关，但选择性自噬降解在调节化疗耐药性中的作用仍不清楚。在这项研究中，我们揭示了ABHD 5通过调节自噬尿嘧啶产量在使CRC对FU敏感性增加中的关键作用。我们证明ABHD 5定位于溶酶体并与PDIA 5相互作用以阻止PDIA 5与RNASET 2相互作用并使RNASET 2失活。ABHD 5缺陷释放PDIA 5以直接与RNASET 2相互作用，并使RNASET 2处于不稳定状态，这损害了RNASET 2介导的自噬尿嘧啶产量，并促进CRC细胞摄取FU作为外源性尿嘧啶，从而增加其对FU的敏感性。我们的研究结果首次揭示了ABHD5在调节溶酶体功能中的新作用，突出了ABHD5作为预测CRC对FU化疗敏感性的引人注目的生物标志物的重要性。
The efficacy of Fluorouracil (FU) in the treatment of colorectal cancer (CRC) is greatly limited by drug resistance. Autophagy has been implicated in chemoresistance, but the role of selective autophagic degradation in regulating chemoresistance remains unknown. In this study, we revealed a critical role of ABHD5 in charging CRC sensitivity to FU via regulating autophagic uracil yield. We demonstrated that ABHD5 localizes to lysosome and interacts with PDIA5 to prevent PDIA5 from interacting with RNASET2 and inactivating RNASET2. ABHD5 deficiency releases PDIA5 to directly interact with RNASET2 and leave RNASET2 in an inactivate state, which impairs RNASET2-mediated autophagic uracil yield and promotes CRC cells to uptake FU as an exogenous uracil, thus increasing their sensitivity to FU. Our findings for the first time reveal a novel role of ABHD5 in regulating lysosome function, highlighting the significance of ABHD5 as a compelling biomarker predicting the sensitivity of CRCs to FU-based chemotherapy.