Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch ...under various stressed condi- tions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramat- ically activated serine biosynthesis pathway （SSP） that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes. Moreover, we demonstrated that SSP activation facilitated by cMye led to elevated glutathione （GSH） production, cell cycle progression and nucleic acid synthesis, which are essential for cell survival and proliferation especially un- der nutrient-deprived conditions. We further uncovered that phosphoserine phosphatase （PSPH）, the final rate-lim- iting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo, and impor- tantly, aberrant expression of PSPH is highly correlated with mortality in hepatocellular carcinoma （HCC） patients, suggesting a potential causal relation between this cMyc-regulated enzyme, or SSP activation in general, and cancer development. Taken together, our results reveal that aberrant expression of cMyc leads to the enhanced SSP activa- tion, an essential part of metabolic switch, to facilitate cancer progression under nutrient-deprived conditions.
Cancer cells are known for their capacity to rewire metabolic pathways to support survival and proliferation under various stress conditions. Ketone bodies, though produced in the liver, are not ...consumed in normal adult liver cells. We find here that ketone catabolism or ketolysis is re-activated in hepatocellular carcinoma （HCC） cells under nutrition deprivation conditions. Mechanistically, 3-oxoacid CoA-transferase 1 （OXCT1）, a rate-limiting ketolytic enzyme whose expression is suppressed in normal adult liver tissues, is re-induced by serum starvation-triggered mTORC2- AKT-SP1 signaling in HCC cells. Moreover, we observe that enhanced ketolysis in HCC is critical for repression of AMPK activation and protects HCC cells from excessive autophagy, thereby enhancing tumor growth. Importantly, analysis of clinical HCC samples reveals that increased OXCT1 expression predicts higher patient mortality. Taken together, we uncover here a novel metabolic adaptation by which nutrition-deprived HCC cells employ ketone bodies for energy supply and cancer progression.
RNA interference (RNAi) is a powerful approach in the treatment of various diseases including cancers. The clinical translation of small interfering RNA (siRNA)-based therapy requires safe and ...efficient delivery vehicles. Here, we report a siRNA nanogels (NG)-based delivery vehicle, which is driven directly by the intercalation between nucleic acid bis-intercalator and siRNA molecules. The intercalation-based siRNA NG exhibits good physiological stability and can enter cells efficiently via different endocytosis pathways. Furthermore, the siRNA NG can not only silence the target genes in vitro but also significantly inhibit the tumor growth in vivo. Therefore, this study provides an intercalation-based strategy for the development of a siRNA delivery platform for cancer therapy. To the best of our knowledge, this is the first report of the intercalation-driven siRNA NG.
Aberrant expression of Lin28 and let-7 has been observed in many human malignancies. However, its functions and underlying mechanisms remain largely elusive. Here we show that aberrant expression of ...Lin28 and let-7 facilitates aerobic glycolysis, or Warburg effect, in cancer cells. Mechanistically, we discover that Lin28A and Lin28B enhance, whereas let-7 suppresses, aerobic glycolysis via targeting pyruvate dehydrogenase kinase 1, or PDK1, in a hypoxia- or hypoxia-inducible factor-1 (HIF-1)-independent manner, illustrating a novel pathway to mediate aerobic glycolysis of cancer cells even in ambient oxygen levels. Importantly, we further demonstrate that PDK1 is critical for Lin28A- and Lin28B-mediated cancer proliferation both in vitro and in vivo, establishing a previously unappreciated mechanism by which Lin28/let-7 axis facilitates Warburg effect to promote cancer progression. Our findings suggest a potential rationale to target PDK1 for cancer therapy in malignancies with aberrant expression of Lin28 and let-7.
LKB1 loss-of-function mutations, observed in ∼30% of human lung adenocarcinomas, contribute significantly to lung cancer malignancy progression. We show that lysyl oxidase (LOX), negatively regulated ...by LKB1 through mTOR-HIF-1α signaling axis, mediates lung cancer progression. Inhibition of LOX activity dramatically alleviates lung cancer malignancy progression. Up-regulated LOX expression triggers excess collagen deposition in Lkb1-deficient lung tumors, and thereafter results in enhanced cancer cell proliferation and invasiveness through activation of β1 integrin signaling. High LOX level and activity correlate with poor prognosis and metastasis. Our findings provide evidence of how LKB1 loss of function promotes lung cancer malignancy through remodeling of extracellular matrix microenvironment, and identify LOX as a potential target for disease treatment in lung cancer patients.
Menin is an enigmatic protein that displays unique ability to either suppress or promote tumorigenesis in a context-dependent manner. The role for Menin to promote oncogenic functions has been ...largely attributed to its essential role in forming the MLL methyltransferase complex, which mediates H3K4me3. Here, we identify an unexpected role of Menin in enhancing the transactivity of oncogene MYC in a way independent of H3K4me3 activity. Intriguingly, we find that Menin interacts directly with the TAD domain of MYC and co-localizes with MYC to E-Box to enhance the transcription of MYC target genes in a P-TEFb-dependent manner. We further demonstrate that, by transcriptionally promoting the expression of MYC target genes in cancer cells, Menin stimulates cell proliferation and cellular metabolism both in vitro and in vivo. Our results uncover a previously unappreciated mechanism by which Menin functions as an oncogenic regulatory factor that is critical for MYC-mediated gene transcription.
Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (MM); however, drug resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, ...we identify, via two in vitro genome-wide CRISPR screens probing Daratumumab resistance, KDM6A as an important regulator of sensitivity to Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Loss of KDM6A leads to increased levels of H3K27me3 on the promoter of CD38, resulting in a marked downregulation in CD38 expression, which may cause resistance to Daratumumab-mediated ADCC. Re-introducing CD38 does not reverse Daratumumab-mediated ADCC fully, which suggests that additional KDM6A targets, including CD48 which is also downregulated upon KDM6A loss, contribute to Daratumumab-mediated ADCC. Inhibition of H3K27me3 with an EZH2 inhibitor resulted in CD38 and CD48 upregulation and restored sensitivity to Daratumumab. These findings suggest KDM6A loss as a mechanism of Daratumumab resistance and lay down the proof of principle for the therapeutic application of EZH2 inhibitors, one of which is already FDA-approved, in improving MM responsiveness to Daratumumab.
PROteolysis TArgeting Chimeras (PROTACs) are an emerging class of promising therapeutic modalities that selectively degrade intracellular proteins of interest by hijacking the ubiquitin‐proteasome ...system. However, the lack of techniques to efficiently transport these degraders to targeted cells and consequently the potential toxicity of PROTACs limit their clinical applications. Here, a strategy of nanoengineered PROTACs, that is, Nano‐PROTACs, is reported, which improves the bioavailability of PROTACs and maximizes their capacity to therapeutically degrade intracellular oncogenic proteins for tumor therapy. The Nano‐PROTACs are developed by encapsulating PROTACs in glutathione (GSH)‐responsive poly(disulfide amide) polymeric (PDSA) nanoparticles and show that ARV@PDSA Nano‐PROTAC, nanoengineered BRD4 degrader ARV‐771, improves BRD4 protein degradation and decreases the downstream oncogene c‐Myc expression. Benefiting from the GSH‐scavenging ability to amply the c‐Myc‐related ferroptosis and cell cycle arrest, this ARV@PDSA Nano‐PROTACs strategy shows superior anti‐tumor efficacy with a low dose administration and good biocompatibility in vivo. The findings reveal the potential of the Nano‐PROTACs strategy to treat a broad range of diseases by dismantling associated pathogenic proteins.
Nanoengineered PROteolysis TArgeting Chimeras (Nano‐PROTACs) are developed with glutathione (GSH)‐responsive polymeric nanoparticles and pioneer their applications in cancer therapy. The Nano‐PROTACs not only address the poor druggability of PROTACs but also enhance the therapeutic efficacy via an intelligent GSH‐scavenging strategy to amplify c‐Myc‐related ferroptosis and cell cycle arrest. This GSH‐scavenging PROTAC nanotechnology would be generalized for treating different malignancies in vivo.
Nature Communications 8: Article number: 15278 (2017); Published 5 May 2017; Updated 30 March 2018 The originally published version of this Article contained errors in Fig. 6. In panel l, the Nile ...Red and Merge images of cells treated with shMYC were inadvertently duplicated from the equivalent images of cells treated with MEN1-sh1 and MEN-sh2 in panel n of the same figure.
Arsenical drugs have achieved hallmark success in treating patients with acute promyelocytic leukemia, but expanding their clinical utility to solid tumors has proven difficult with the contradiction ...between the therapeutic efficacy and the systemic toxicity. Here, leveraging efforts from materials science, biocompatible PEGylated arsenene nanodots (AsNDs@PEG) with high monoelemental arsenic purity that can selectively and effectively treat solid tumors are synthesized. The intrinsic selective killing effect of AsNDs@PEG is closely related to high oxidative stress in tumor cells, which leads to an activated valence‐change of arsenic (from less toxic As0 to severely toxic oxidation states), followed by decreased superoxide dismutase activity and massive reactive oxygen species (ROS) production. These effects occur selectively within cancer cells, causing mitochondrial damage, cell‐cycle arrest, and DNA damage. Moreover, AsNDs@PEG when applied in a multi‐drug combination strategy with β‐elemene, a plant‐derived anticancer drug, achieves synergistic antitumor outcomes, and its newly discovered on‐demand photothermal properties facilitate the elimination of the tumors without recurrence, potentially further expanding its clinical utility. In line of the practicability for a large‐scale fabrication and negligible systemic toxicity of AsNDs@PEG (even at high doses and with repetitive administration), a new‐concept arsenical drug with high therapeutic efficacy for selective solid tumor therapy is provided.
PEGylated arsenene nanodots (AsNDs@PEG) with high monoelemental arsenic purity and negligible systemic toxicity are identified as a new‐concept arsenical drug for selectively treating solid tumors through the valence‐change of arsenic to generate toxic oxidation states and on‐demand photothermal therapy. This work can encourage a fast‐paced clinical translation of arsenene for tumor treatments with potentially low attrition rates.
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