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.
Cancer cells re-program their metabolic machinery to meet the requirements of malignant transformation and progression. Glutaminase 1 (GLS1) was traditionally known as a mitochondrial enzyme that hydrolyzes glutamine into glutamate and fuels rapid proliferation of cancer cells. However, emerging evidence has now revealed that GLS1 might be a novel oncogene involved in tumorigenesis and progression of human cancers. In this study, we sought to determine whether GLS1 implicated in invasion and metastasis of colorectal carcinoma, and its underlying molecular mechanism. By analyzing a large set of clinical data from online datasets, we found that GLS1 is overexpressed in cancers compared with adjacent normal tissues, and associated with increased patient mortality. Immunohistochemical analysis of GLS1 staining showed that high GLS1 expression is significantly correlated with lymph node metastasis and advanced clinical stage in colorectal cancer patients. To investigate the underlying mechanism, we analyzed the Cancer Genome Atlas database and found that GLS1 mRNA expression is associated with a hypoxia signature, which is correlated with an increased risk of metastasis and mortality. Furthermore, reduced oxygen availability increases GLS1 mRNA and protein expression, due to transcriptional activation by hypoxia-inducible factor 1. GLS1 expression in colorectal cancer cells is required for hypoxia-induced migration and invasion in vitro and for tumor growth and metastatic colonization in vivo.
SUMMARY How cancer cells shift metabolism to aerobic glycolysis is largely unknown. Here we show that deficiency of α/β-hydrolase domain-containing-5 (Abhd5), an intracellular lipolytic activator that is also known as comparative gene identification-58 (CGI-58), promotes this metabolic shift and enhances malignancies of colorectal carcinomas (CRCs). Silencing of Abhd5 in normal fibroblasts induces malignant transformation. Intestine-specific knockout of Abhd5 in ApcMin/+ mice robustly increases tumorigenesis and malignant transformation of adenomatous polyps. In colon cancer cells, Abhd5 deficiency induces epithelial-mesenchymal transition by suppressing the AMPKα-p53 pathway, which is attributable to increased aerobic glycolysis. In human CRCs, Abhd5 expression falls substantially and correlates negatively with malignant features. Our study is the first to link Abhd5 to CRC pathogenesis. It suggests that cancer cells may develop aerobic glycolysis by suppressing Abhd5-mediated intracellular lipolysis.
Metabolic reprogramming in stromal cells plays an essential role in regulating tumour growth. The metabolic activities of tumour-associated macrophages (TAMs) in colorectal cancer (CRC) are incompletely characterized. Here, we identify TAM-derived factors and their roles in the development of CRC. We demonstrate that ABHD5, a lipolytic co-activator, is ectopically expressed in CRC-associated macrophages. We demonstrate in vitro and in mouse models that macrophage ABHD5 potentiates growth of CRC cells. Mechanistically, ABHD5 suppresses spermidine synthase (SRM)-dependent spermidine production in macrophages by inhibiting the reactive oxygen species-dependent expression of C/EBPɛ, which activates transcription of the srm gene. Notably, macrophage-specific ABHD5 transgene-induced CRC growth in mice can be prevented by an additional SRM transgene in macrophages. Altogether, our results show that the lipolytic factor ABHD5 suppresses SRM-dependent spermidine production in TAMs and potentiates the growth of CRC. The ABHD5/SRM/spermidine axis in TAMs might represent a potential target for therapy.
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