ABSTRACT
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.
Subject(s)
1-Acylglycerol-3-Phosphate O-Acyltransferase/metabolism , Antimetabolites, Antineoplastic/pharmacology , Autophagy , Colorectal Neoplasms/therapy , Fluorouracil/pharmacology , 1-Acylglycerol-3-Phosphate O-Acyltransferase/genetics , Animals , Antimetabolites, Antineoplastic/therapeutic use , Biomarkers, Tumor/metabolism , Carcinogenesis/pathology , Chemotherapy, Adjuvant/methods , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Datasets as Topic , Disease Progression , Disease-Free Survival , Drug Resistance, Neoplasm , Fluorouracil/therapeutic use , Gene Knockdown Techniques , HCT116 Cells , Humans , Kaplan-Meier Estimate , Lysosomes/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, Nude , Mice, SCID , Ribonucleases/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Uracil/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Human telomerase reverse transcriptase (hTERT) has been found to be closely related to tumor transformation, growth, and metastasis. Thus, the delivery of hTERT small interfering RNA (siRNA) is an important approach for cancer gene therapy. However, the single anticancer effect of gene silencing is often limited by poor specificity or low efficiency in siRNA delivery and release. In this work, we present small and thin black phosphorus (BP) nanosheets as a biodegradable delivery system for hTERT siRNA. The BP nanosheets prepared with poly(ethylene glycol) (PEG) and polyethylenimine (PEI) modification (PPBP), exhibited high siRNA loading capacity and robust cell uptake. The PPBP nanosheets also exhibited potent photodynamic therapy/photothermal therapy (PDT/PTT) activities when exposed to different wavelengths of laser irradiation. More importantly, PPBP nanosheets underwent a gradual degradation when presented in a mixture of low pH and reactive oxygen species (ROS)-rich environment. The degradation of PPBP was strengthened especially after local and minimal invasive PDT treatment, because of excessive ROS production. Further delivery and release of siRNA to the cytoplasm for gene silencing was achieved by PEI-aided escape from the acidic lysosome. Thus, PPBP-siRNA efficiently inhibited tumor growth and metastasis by specific delivery of hTERT siRNA and a synergistic combination of targeted gene therapy, PTT and PDT.