Critical role of ASCT2-mediated amino acid metabolism in promoting leukaemia development and progression

Amino acid (AA) metabolism is involved in diverse cellular functions, including cell survival and growth, however it remains unclear how it regulates normal hematopoiesis versus leukemogenesis. Here, we report that knockout of Slc1a5 (ASCT2), a transporter of neutral AAs, especially glutamine, results in mild to moderate defects in bone marrow and mature blood cell development under steady state conditions. In contrast, constitutive or induced deletion of Slc1a5 decreases leukemia initiation and maintenance driven by the oncogene MLL-AF9 or Pten deficiency. Survival of leukemic mice is prolonged following Slc1a5 deletion, and pharmacological inhibition of ASCT2 also decreases leukemia development and progression in xenograft models of human acute myeloid leukemia. Mechanistically, loss of ASCT2 generates a global effect on cellular metabolism, disrupts leucine influx and mTOR signaling, and induces apoptosis in leukemic cells. Given the substantial difference in reliance on ASCT2-mediated AA metabolism between normal and malignant blood cells, this in vivo study suggests ASCT2 as a promising therapeutic target for the treatment of leukemia

Design of Saline Gel Coil for Inner Heating of Electrolyte Solution and Liquid Foods under Induced Electric Field

As an emerging electrotechnology, induced electric field has attracted extensive attention in the development of innovative heat treatment equipment. In this study, a resistance heating unit based on induced electric field was built for inner heating of aqueous electrolyte solutions as well as liquid foods, such as vinegar. NaCl solutions and liquid foods with different conductivity were used to investigate the thermal effect and temperature rise of samples. Saline gel composed of 3% agar powder and 20% NaCl acted as a coil of conductor for inducing high-level output voltage. The utilization of the saline gel coil significantly improved the power conversion efficiency of the heating unit as well as the heating rate. The results revealed that duty cycle and applied frequency had immediate impact on the efficiency of inner heating. Additionally, the rate of temperature rise was proportional to the conductivity of the sample. The temperature of 200 mL NaCl solution (0.6%) increased from 25 °C to 100 °C in 3 min at 40% duty cycle and 60 kHz of applied frequency, and it was a circulating-flow process. The maximum temperature rise of black vinegar was 39.6 °C in 15 s at 60 kHz and 60% duty cycle, while that of white vinegar was 32.2 °C in 30 s under same conditions, whereas it was a continuous-flow process. This novel heating system has realized the inner heating of liquid samples

Catalysis-Based Cataluminescent and Conductometric Gas Sensors: Sensing Nanomaterials, Mechanism, Applications and Perspectives

Gas environment detection has become more urgent and significant, for both industrial manufacturing and environment monitoring. Gas sensors based on a catalytically-sensing mechanism are one of the most important types of devices for gas detection, and have been of great interest during the past decades. However, even though many efforts have contributed to this area, some great challenges still remain, such as the development of sensitively and selectively sensing catalysts. In this review, two representative catalysis-based gas sensors, cataluminescent and conductometric sensors, the basis of optical and electric signal acquisition, respectively, are summarized comprehensively. The current challenges have been presented. Recent research progress on the working mechanism, sensing nanomaterials, and applications reported by our group and some other researchers have been discussed systematically. The future trends and prospects of the catalysis-based gas sensors have also been presented

Highly Sensitive SERS Detection of Hg²⁺ Ions in Aqueous Media Using Gold Nanoparticles/Graphene Heterojunctions

Gold nanoparticles (AuNPs)/reduced graphene oxide (rGO) heterojunctions were synthesized directly on SiO₂/Si substrates via a seed-assisted growth process. The in situ chemical fabrication strategy has been proven to be quite simple and efficient for generating highly active surface-enhanced Raman scattering (SERS) substrates due to synergistic enhanced protocol from rGO and AuNPs. The SERS substrates with AuNPs/rGO heterojunctions have been utilized for trace analysis of mercury­(II) ions via thymine–Hg²⁺–thymine coordination. Thereby, very low limits of detection, i.e., 0.1 nM or 20 ppt for Hg²⁺, can be achieved in contrast with some other SERS subsrtates, which suggests that the heterojunctions are appropriate as versatile surface-enhanced substrates applied in chemical sensing or biosensing

Reducing Chemotherapy-Induced DNA Damage via nAChR-Mediated Redox Reprograming—A New Mechanism for SCLC Chemoresistance Boosted by Nicotine

Up to 60% of patients with small cell lung cancer (SCLC) continue to smoke, which is associated with worse clinical outcomes. Platinum-based chemotherapies, in combination with topoisomerase inhibitors, are first-line therapies for SCLC, with rapid chemoresistance as a major barrier. We provided evidence in this study that nicotine and its major metabolite, cotinine, at physiologically relevant concentrations, reduced the efficacy of platinum-based chemotherapies and facilitated chemoresistance in SCLC cells. Mechanistically, nicotine or cotinine reduced chemotherapy-induced DNA damage by modulating cellular redox processes, with nAChRs as the upstream targets. Surprisingly, cisplatin treatment alone also increased the levels of nAChRs in SCLC cells, which served as a self-defense mechanism against platinum-based therapies. These discoveries were confirmed in long-term in vitro and in vivo studies. Collectively, our results depicted a novel and clinically important mechanism of chemoresistance in SCLC treatment: nicotine exposure significantly compromises the efficacy of platinum-based chemotherapies in SCLC treatment by reducing therapy-induced DNA damage and accelerating chemoresistance acquisition. The results also emphasized the urgent need for tobacco cessation and the control of NRT use for SCLC management

ROS-mediated SRMS activation confers platinum resistance in ovarian cancer.

Ovarian cancer is the leading cause of death among gynecological malignancies. Checkpoint blockade immunotherapy has so far only shown modest efficacy in ovarian cancer and platinum-based chemotherapy remains the front-line treatment. Development of platinum resistance is one of the most important factors contributing to ovarian cancer recurrence and mortality. Through kinome-wide synthetic lethal RNAi screening combined with unbiased datamining of cell line platinum response in CCLE and GDSC databases, here we report that Src-Related Kinase Lacking C-Terminal Regulatory Tyrosine And N-Terminal Myristylation Sites (SRMS), a non-receptor tyrosine kinase, is a novel negative regulator of MKK4-JNK signaling under platinum treatment and plays an important role in dictating platinum efficacy in ovarian cancer. Suppressing SRMS specifically sensitizes p53-deficient ovarian cancer cells to platinum in vitro and in vivo. Mechanistically, SRMS serves as a sensor for platinum-induced ROS. Platinum treatment-induced ROS activates SRMS, which inhibits MKK4 kinase activity by directly phosphorylating MKK4 at Y269 and Y307, and consequently attenuates MKK4-JNK activation. Suppressing SRMS leads to enhanced MKK4-JNK-mediated apoptosis by inhibiting MCL1 transcription, thereby boosting platinum efficacy. Importantly, through a drug repurposing strategy, we uncovered that PLX4720, a small molecular selective inhibitor of B-RafV600E, is a novel SRMS inhibitor that can potently boost platinum efficacy in ovarian cancer in vitro and in vivo. Therefore, targeting SRMS with PLX4720 holds the promise to improve the efficacy of platinum-based chemotherapy and overcome chemoresistance in ovarian cancer

The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer.

Loss of LKB1 is associated with increased metastasis and poor prognosis in lung cancer, but the development of targeted agents is in its infancy. Here we report that a glutaminolytic enzyme, glutamate dehydrogenase 1 (GDH1), upregulated upon detachment via pleomorphic adenoma gene 1 (PLAG1), provides anti-anoikis and pro-metastatic signals in LKB1-deficient lung cancer. Mechanistically, the GDH1 product α-KG activates CamKK2 by enhancing its substrate AMPK binding, which contributes to energy production that confers anoikis resistance. The effect of GDH1 on AMPK is evident in LKB1-deficient lung cancer, where AMPK activation predominantly depends on CamKK2. Targeting GDH1 with R162 attenuated tumor metastasis in patient-derived xenograft model and correlation studies in lung cancer patients further validated the clinical relevance of our finding. Our study provides insight into the molecular mechanism by which GDH1-mediated metabolic reprogramming of glutaminolysis mediates lung cancer metastasis and offers a therapeutic strategy for patients with LKB1-deficient lung cancer

p90 RSK2 Mediates Antianoikis Signals by both Transcription-Dependent and -Independent Mechanisms

How invasive and metastatic tumor cells evade anoikis induction remains unclear. We found that knockdown of RSK2 sensitizes diverse cancer cells to anoikis induction, which is mediated through phosphorylation targets including apoptosis signal-regulating kinase 1 (ASK1) and cyclic AMP (cAMP) response element-binding protein (CREB). We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding. Moreover, the RSK2→CREB signaling pathway provides antianoikis protection by regulating gene expression of protein effectors that are involved in cell death regulation, including the antiapoptotic factor protein tyrosine kinase 6 (PTK6) and the proapoptotic factor inhibitor-of-growth protein 3 (ING3). PTK6 overexpression or ING3 knockdown in addition to ASK1 knockdown further rescued the increased sensitivity to anoikis induction in RSK2 knockdown cells. These data together suggest that RSK2 functions as a signal integrator to provide antianoikis protection to cancer cells in both transcription-independent and -dependent manners, in part by signaling through ASK1 and CREB, and contributes to cancer cell invasion and tumor metastasis