Metastasis is the major cause of treatment failure in cancer patients and of cancer-related deaths. This editorial discusses how cancer metastasis may be better perceived and controlled. Based on ...big-data analyses, a collection of 150 important pro-metastatic genes was studied. Using The Cancer Genome Atlas datasets to re-analyze the effect of some previously reported metastatic genes-e.g., JAM2, PPARGC1A, SIK2, and TRAF6-on overall survival of patients with renal and liver cancers, we found that these genes are actually protective factors for patients with cancer. The role of epithelial-mesenchymal transition (EMT) in single-cell metastasis has been well-documented. However, in metastasis caused by cancer cell clusters, EMT may not be necessary. A novel role of epithelial marker E-cadherin, as a sensitizer for chemoresistant prostate cancer cells by inhibiting Notch signaling, has been found. This editorial also discusses the obstacles for developing anti-metastatic drugs, including the lack of high-throughput technologies for identifying metastasis inhibitors, less application of animal models in the pre-clinical evaluation of the leading compounds,and the need for adjustments in clinical trial design to better reflect the anti-metastatic efficacy of new drugs.We are confident that by developing more effective high-throughput technologies to identify metastasis inhibitors,we can better predict, prevent, and treat cancer metastasis.
Metformin, an inexpensive and well-tolerated oral agent commonly used in the first-line treatment of type 2 diabetes,has become the focus of intense research as a candidate anticancer agent. Here, we ...discuss the potential of metformin in cancer therapeutics, particularly its functions in multiple signaling pathways, including AMP-activated protein kinase, mammalian target of rapamycin, insulin-like growth factor, c-Jun N-terminal kinase/mitogen-activated protein kinase (p38 MAPK), human epidermal growth factor receptor-2, and nuclear factor kappaB pathways. In addition, cutting-edge targeting of cancer stem cells by metformin is summarized.
Dietary fructose is primarily metabolized in the liver. Here we demonstrate that, compared with normal hepatocytes, hepatocellular carcinoma (HCC) cells markedly reduce the rate of fructose ...metabolism and the level of reactive oxygen species, as a result of a c-Myc-dependent and heterogeneous nuclear ribonucleoprotein (hnRNP) H1- and H2-mediated switch from expression of the high-activity fructokinase (KHK)-C to the low-activity KHK-A isoform. Importantly, KHK-A acts as a protein kinase, phosphorylating and activating phosphoribosyl pyrophosphate synthetase 1 (PRPS1) to promote pentose phosphate pathway-dependent de novo nucleic acid synthesis and HCC formation. Furthermore, c-Myc, hnRNPH1/2 and KHK-A expression levels and PRPS1 Thr225 phosphorylation levels correlate with each other in HCC specimens and are associated with poor prognosis for HCC. These findings reveal a pivotal mechanism underlying the distinct fructose metabolism between HCC cells and normal hepatocytes and highlight the instrumental role of KHK-A protein kinase activity in promoting de novo nucleic acid synthesis and HCC development.
Background
Ultrahigh dose‐rate irradiation (FLASH‐IR) was reported to be efficient in tumor control while reducing normal tissue radiotoxicity. However, the mechanism of such phenomenon is still ...unclear. Besides, the FLASH experiments using high energy X‐ray, the most common modality in clinical radiotherapy, are rarely reported. This study aims to investigate the radiobiological response using 6 MV X‐ray FLASH‐IR or conventional dose‐rate IR (CONV‐IR).
Methods
The superconducting linac of Chengdu THz Free Electron Laser (CTFEL) facility was used for FLASH‐IR, a diamond radiation detector and a CeBr3 scintillation detector were used to monitor the time structure and dose rate of FLASH pulses. BALB/c nude mice received whole abdominal 6 MV X‐ray FLASH‐IR or CONV‐IR, the prescribed dose was 15 Gy or 10 Gy and the delivered absolute dose was monitored with EBT3 films. The mice were either euthanized 24 h post‐IR to evaluate acute tissue responses or followed up for 6 weeks to observe late‐stage responses and survival probability. Complete blood count, histological analyses, and measurement of cytokine expression and redox status were performed.
Results
The mean dose rate of >150 Gy/s and instantaneous dose rate of >5.5 × 105 Gy/s was reached in FLASH‐IR at the center of mice body. After 6 weeks’ follow‐up of mice that received 15 Gy IR, the FLASH group showed faster body weight recovery and higher survival probability than the CONV group. Histological analysis showed that FLASH‐IR induced less acute intestinal damage than CONV‐IR. Complete blood count and cytokine concentration measurement found that the inflammatory blood cell counts and pro‐inflammatory cytokine concentrations were elevated at the acute stage after both FLASH‐IR and CONV‐IR. However, FLASH irradiated mice had significantly fewer inflammatory blood cells and diminished pro‐inflammatory cytokine at the late stage. Moreover, higher reactive oxygen species (ROS) signal intensities but significantly reduced lipid peroxidation were found in the FLASH group than in the CONV group in the acute stage.
Conclusions
The radioprotective effect of 6 MV X‐ray FLASH‐IR was observed. The differences in inflammatory responses and redox status between the two groups may be the factors responsible for reduced radiotoxicities following FLASH‐IR. Further studies are required to thoroughly evaluate the impact of ROS on FLASH effect.
The broad spectrum kinase inhibitor sunitinib is a first-line therapy for advanced clear cell renal cell carcinoma (ccRCC), a deadly form of kidney cancer. Unfortunately, most patients develop ...sunitinib resistance and progressive disease after about 1 year of treatment. In this study, we evaluated the mechanisms of resistance to sunitinib to identify the potential tactics to overcome it. Xenograft models were generated that mimicked clinical resistance to sunitinib. Higher microvessel density was found in sunitinib-resistant tumors, indicating that an escape from antiangiogenesis occurred. Notably, escape coincided with increased secretion of interleukin-8 (IL-8) from tumors into the plasma, and coadministration of an IL-8 neutralizing antibody resensitized tumors to sunitinib treatment. In patients who were refractory to sunitinib treatment, IL-8 expression was elevated in ccRCC tumors, supporting the concept that IL-8 levels might predict clinical response to sunitinib. Our results reveal IL-8 as an important contributor to sunitinib resistance in ccRCC and a candidate therapeutic target to reverse acquired or intrinsic resistance to sunitinib in this malignancy.
Notch pathway is a highly conserved cell signaling system that plays very important roles in controlling multiple cell differentiation processes during embryonic and adult life. Multiple lines of ...evidence support the oncogenic role of Notch signaling in several human solid cancers; however, the pleiotropic effects and molecular mechanisms of Notch signaling inhibition on nasopharyngeal carcinoma (NPC) remain unclear. In this study, we evaluated Notch1 expression in NPC cell lines (CNE1, CNE2, SUNE1, HONE1, and HK1) by real‐time quantitative PCR and Western blot analysis, and we found that CNE1 and CNE2 cells expressed a higher level of Notch1 compared with HONE1, SUNE1, and HK1 cells. Then Notch1 expression was specifically knocked down in CNE1 and CNE2 cells by Notch1 short hairpin RNA (shRNA). In Notch1 knockdown cells, cell proliferation, migration, and invasion were significantly inhibited. The epithelial‐mesenchymal transition of tumor cells was reversed in Notch1‐shRNA‐transfected cells, accompanied by epithelioid‐like morphology changes, increased protein levels of E‐cadherin, and decreased expression of vimentin. In addition, knockdown of Notch1 markedly inhibited the expression of urokinase plasminogen activator (uPA) and its receptor uPAR, and chemokines C‐C motif chemokine ligand 2 and C‐X‐C motif chemokine ligand 16, indicating that these factors are downstream targets of Notch1. Furthermore, deleting uPA expression had similar effects as Notch1. Finally, knockdown of Notch1 significantly diminished CNE1 cell growth in a murine model concomitant with inhibition of cell proliferation and induction of apoptosis. These results suggest that Notch1 may become a novel therapeutic target for the clinical treatment of NPC.
Approximately 30% of patients with Epstein-Barr virus (EBV)-positive advanced nasopharyngeal carcinoma (NPC) display chemoresistance to cisplatin-based regimens, but the underlying mechanisms are ...unclear. The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1), a functional homologue of the tumor necrosis factor receptor family, contributes substantially to the oncogenic potential of EBV through the activation of multiple signaling pathways, and it is closely associated with a poorer prognosis for NPC. Recent studies show that EBV infection can induce the expression of many cellular miRNAs, including microRNA-21, a biomarker for chemoresistance. However, neither a link between LMP1 expression and miR-21 upregulation nor their cross talk in affecting chemoresistance to cisplatin have been reported. Here, we observed that stable LMP1-transformed NPC cells were less sensitive to cisplatin treatment based on their proliferation, colony formation, the IC50 value of cisplatin and the apoptosis index. Higher levels of miR-21 were found in EBV-carrying and LMP1-positive cell lines, suggesting that LMP1 may be linked to miR-21 upregulation. These data were confirmed by our results that exogenous LMP1 increased miR-21 in both transiently and stably LMP1-transfected cells, and the knock down of miR-21 substantially reversed the resistance of the NPC cells to cisplatin treatment. Moreover, the proapoptotic factors programmed cell death 4 (PDCD4) and Fas ligand (Fas-L), which were negatively regulated by miR-21, were found to play an important role in the program of LMP1-dependent cisplatin resistance. Finally, we demonstrated that LMP1 induced miR-21 expression primarily by modulating the PI3K/AKT/FOXO3a signaling pathway. Taken together, we revealed for the first time that viral LMP1 triggers the PI3K/Akt/FOXO3a pathway to induce human miR-21 expression, which subsequently decreases the expression of PDCD4 and Fas-L, and results in chemoresistance in NPC cells.
Nutrients are not only organic compounds fueling bioenergetics and biosynthesis, but also key chemical signals controlling growth and metabolism. Nutrients enormously impact the production of ...reactive oxygen species (ROS), which play essential roles in normal physiology and diseases. How nutrient signaling is integrated with redox regulation is an interesting, but not fully understood, question. Herein, we report that superoxide dismutase 1 (SOD1) is a conserved component of the mechanistic target of rapamycin complex 1 (mTORC1) nutrient signaling. mTORC1 regulates SOD1 activity through reversible phosphorylation at S39 in yeast and T40 in humans in response to nutrients, which moderates ROS level and prevents oxidative DNA damage. We further show that SOD1 activation enhances cancer cell survival and tumor formation in the ischemic tumor microenvironment and protects against the chemotherapeutic agent cisplatin. Collectively, these findings identify a conserved mechanism by which eukaryotes dynamically regulate redox homeostasis in response to changing nutrient conditions.
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•SOD1 is a conserved effector of mTORC1 signaling in eukaryotic cells•Nutrients restrain SOD1 through mTORC1-dependent phosphorylation to promote growth•Starvation stimulates SOD1 activity to prevent oxidative damage and enhance survival•SOD1 enhances cancer cell survival and chemoresistance in ischemic microenvironment
Tsang et al. show that SOD1 phosphorylation by mTOR provides a dynamic mechanism for eukaryotic cells to respond to changing nutrient conditions. It permits rapid growth in rich nutrients, while it confers resistance to oxidative stress during starvation. This mechanism contributes to cancer cell survival and chemoresistance in the ischemic microenvironment.
Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer, presenting in 80% of these ...patients, and it is one of the primary causes of morbidity and mortality associated with cancer. Additionally, although many people with cachexia show hypermetabolism, the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell-based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo. Therefore, fatty acid-induced oxidative stress could be targeted to prevent cancer-induced cachexia.
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