The radioresistance induced by hypoxia is the major obstacle in the successful treatment of cancer radiotherapy. p21 was initially identified as a widespread inhibitor of cyclin‐dependent kinases, ...through which mediates the p53‐dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. In this study, we discovered a novel function of p21, which participated in the regulation of metabolic pathways under hypoxia. We found that p21 was upregulated in glioblastoma (GBM) cells under hypoxic conditions, which enhanced the radioresistance of GBM cells. In principle, HIF‐1α is bound directly to the hypoxia response elements (HREs) of the p21 promoter to enhance its transcription activity, in turn, p21 also promoted the transcription of HIF‐1α at the mRNA level and maintained HIF‐1α function under oxygen deficiency. The positive correlation between p21 and HIF‐1α augmented Glut1/LDHA‐mediated glycolysis and aggravated the radioresistance of GBM cells. Thus, our results constructed a positive feedback circuit comprising p21/HIF‐1α that might play a key role in enhancing the radioresistance of GBM under hypoxia.
Polygalacturonase-inhibiting proteins (PGIPs) are plant defense proteins. To date, no spatial distribution of PGIPs and interaction between PGIPs and nitric oxide (NO) in plant were described. Here, ...we first reported the full-length cDNA sequence of PGIP of Chorispora bungeana (CbPGIP1). Notably, immunofluorescence localization showed that the CbPGIP was evenly distributed in leaves but it was mainly localized in epidermis and vascular bundle in stems and roots. Further studies indicated that CbPGIP had higher abundance in roots than in stems and leaves. Conversely, the bulk PGIP of C. bungeana showed a higher activity in leaves than in stems and roots. In addition, quantitative real-time polymerase chain reaction demonstrated that CbPGIP1 expression was induced by Stemphylium solani, salicylic acid (SA), 4, −4°C and NO. This is a first report attempting to predict if NO can induce the PGIP expression. Taken together, these findings showed that the gene was spatially regulated and NO and SA might take part in CbPGIP1 expression induced by biotic and abiotic stresses. This study highlighted the potential importance of CbPGIP1 and NO in plant resistance.
Hydrogen sulfide (H2S) plays an important role as a signaling compound (gasotransmitter) in living systems. However, the development of an efficient imaging chemosensor of H2S in live animals is a ...challenging field for chemists. Herein, a novel peptide-based fluorescence chemosensor L-Cu was designed and synthesized on the basis of the copper chelating with the peptide ligand (FITC–Ahx–Ser–Pro–Gly–His–NH2, L), and its H2S sensing ability has been evaluated both in living cells and zebrafish. The peptide backbone and Cu2+-removal sensing mechanism are used to deliver rapid response time, high sensitivity, and good biocompatibility. After a fast fluorescence quench by Cu2+ coordinated with L, the fluorescence of L is recovered by adding S2− to form insoluble copper sulfide in aqueous solution with a detection limit for hydrogen sulfide measured to be 31nM. Furthermore, the fluorescence chemosensor L-Cu showed excellent cell permeation and low biotoxicity to realize the intracellular biosensing, L-Cu has also been applied to image hydrogen sulfide in live zebrafish larvae. We expect that this peptide-based fluorescence chemosensor L-Cu can be used to study H2S-related chemical biology in physiological and pathological events.
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Emerging evidence indicates that reprogramming of energy metabolism involving disturbances in energy production from a defect in cellular respiration with a shift to glycolysis is a core hallmark of ...cancer. Alterations in cancer cell energy metabolism are linked to abnormalities in mitochondrial function. Mitochondrial dysfunction of cancer cells includes increased glycolysis, decreased apoptosis, and resistance to radiotherapy. The study was designed for two main points: firstly, to investigate whether exogenous functional mitochondria can transfer into glioma cells and explore the underlying molecular mechanisms from the perspective of endocytosis; secondly, to further verify whether the mitochondrial transplantation is able to rescue aerobic respiration, attenuate the Warburg effect and enhance the radiosensitivity of gliomas.
Mitochondria were isolated from normal human astrocytes (HA) and immediately co-incubated with starved human glioma cells (U87). Confocal microscopy and gene sequencing were performed to evaluate the ability of isolated mitochondria internalization into U87 cells. The interaction between endocytosis and isolated mitochondria transfer were captured by 3D tomographic microscopy and transmission electron microscopy. NAD
, CD38, cADPR and Ca
release were determined by commercial kits, western blot, HLPC-MS and Fluo-3 AM respectively. PCR array expression profiling and Seahorse XF analysis were used to evaluate the effect of mitochondrial transplantation on energy phenotypes of U87 cells. U87 cells and U87 xenografts were both treated with mitochondrial transplantation, radiation, or a combination of mitochondrial transplantation and radiation. Apoptosis
and
were detected by cytochrome C, cleaved caspase 9 and TUNEL staining.
We found that mitochondria from HA could be transferred into starved U87 cells by simple co-incubation. Starvation treatment slowed the rate of glycolysis and decreased the transformation of NAD
to NADH in U87 cells. A large amount of accumulated NAD
was released into the extracellular space. CD38 is a member of the NAD
glycohydrolase family that catalyzes the cyclization of extracellular NAD
to intracellular cADPR. cADPR triggered release of Ca
to promote cytoskeleton remodeling and plasma membrane invagination. Thus, endocytosis involving isolated mitochondria internalization was mediated by NAD
-CD38-cADPR-Ca
signaling. Mitochondrial transfer enhanced gene and protein expression related to the tricarboxylic acid (TCA) cycle, increased aerobic respiration, attenuated glycolysis, reactivated the mitochondrial apoptotic pathway, inhibited malignant proliferation of U87 cells. Isolated mitochondria injected into U87 xenograft tumors also entered cells, and inhibited glioma growth in nude mice. Mitochondrial transplantation could enhance the radiosensitivity of gliomas
and
.
These findings suggested that starvation-induced endocytosis via NAD
-CD38-cADPR-Ca
signaling could be a new mechanism of mitochondrial transplantation to rescue aerobic respiration and attenuate the Warburg effect. This mechanism could be a promising approach for radiosensitization.
Poly (rC)‐binding protein 1 (PCBP1), an RNA‐ or DNA‐binding protein with a relative molecular weight of 38 kDa, which is characterized by downregulation in many cancer types. Numerous cases have ...indicated that PCBP1 could be considered as a tumor suppressor to inhibit tumorigenesis, development, and metastasis. In the current review, we described the multilevel regulatory roles of PCBP1, including gene transcription, alternative splicing, and translation of many cancer‐related genes. Additionally, we also provided a brief overview about the inhibitory effect of PCBP1 on most common tumors. More importantly, we summarized the current research status about PCBP1 in hypoxic microenvironment, autophagy, apoptosis, and chemotherapy of cancer cells, aiming to clarify the molecular mechanisms of PCBP1 in cancer. Taken together, in‐depth study of PCBP1 in cancer may provide new ideas for cancer therapy.
Polygalacturonase-inhibiting proteins (PGIPs) are plant proteins believed to play an important role in the defense against plant pathogen fungals. PGIPs are glycoproteins located in plant cell wall ...which reduce the hydrolytic activity of polygalacturonases (PGs), limit the growth of plant pathogens, and also elicit defense responses in plant. Furthermore, PGIPs belong to the super family of leucine reach repeat (LRR) proteins which also include the products of several plant resistance genes. Many of the studies show the PGIP properties, molecular characteristics, and PGIP gene expression induced by some elicitors. Some of the studies review individual PGIP gene expression in different signal transduction pathways. This article summarizes the properties, different signal transduction mechanisms, detecting methods, transgenic plants, and function of PGIP. It also presents PGIP gene expression in different stages of maturity, tissues, and varieties. The review especially reports the particular PGIP gene expression induced by different biotic and abiotic stresses, offers some questions, and prospects the future study, which are needed in order to develop efficient strategies for disease-resistant plants. They may be useful for genetic engineering to obtain transgenic plants with increased tolerance to fungal infection, which decrease the use of insecticide.
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