Oncogene‐induced hyper‐proliferation in cancer cells is accompanied by the onset of different stresses, including DNA‐replication stress, metabolic stress and oxidative stress. Excessive accumulation ...of reactive oxygen species (ROS) plays a pivotal and contradictory role in tumor progression. ROS dictates a multitude of cell signaling pathways to facilitate the malignant transformation of tumor cells. In the meantime, oxidative burden in tumor cells mandates reinforcing antioxidant capacity to mitigate detrimental damages. The addiction to oxidative stress and increased iron demands in cancer cells also impinges on the sensitivity of ferroptosis. Targeting redox homeostasis and ferroptosis to overcome drug resistance in cancer treatment has become an attractive research topic. However, the roles of oncogenic signaling in redox regulation and ferroptosis have not been comprehensively discussed. In this review, we summarize current knowledge regarding the interplay between redox regulation and ferroptosis in the context of cancer biology. We emphasize the implication of oncogenic signaling in redox homeostasis and ferroptosis regulation. We also provide an overview of strategies targeting oxidative stress and ferroptosis in cancer treatment.
Insulin-like growth factor binding protein-3 (IGFBP-3) is a multifunctional molecule which is closely related to cell growth, apoptosis, angiogenesis, metabolism and senescence. It combines with ...insulin-like growth factor-I (IGF-I) to form a complex (IGF-I/IGFBP-3) that can treat growth hormone insensitivity syndrome (GHIS) and reduce insulin requirement in patients with diabetes. IGFBP-3 alone has been shown to have anti-proliferation effect on numerous cancer cells.
We reported here an expression method to produce functional recombinant human IGFBP-3 (rhIGFBP-3) in transgenic rice grains. Protein sorting sequences, signal peptide and endoplasmic reticulum retention tetrapeptide (KDEL) were included in constructs for enhancing rhIGFBP-3 expression. Western blot analysis showed that only the constructs with signal peptide were successfully expressed in transgenic rice grains. Both rhIGFBP-3 proteins, with or without KDEL sorting sequence inhibited the growth of MCF-7 human breast cancer cells (65.76 ± 1.72% vs 45.00 ± 0.86%, p < 0.05; 50.84 ± 1.97% vs 45.00 ± 0.86%, p < 0.01 respectively) and HT-29 colon cancer cells (65.14 ± 3.84% vs 18.01 ± 13.81%, p < 0.05 and 54.7 ± 9.44% vs 18.01 ± 13.81%, p < 0.05 respectively) when compared with wild type rice.
These findings demonstrated the feasibility of producing biological active rhIGFBP-3 in rice using a transgenic approach, which will definitely encourage more research on the therapeutic use of hIGFBP-3 in future.
Emerging evidence implicates a role of the gut microbiota in colorectal cancer (CRC). Peptostreptococcus anaerobius (P. anaerobius) is an anaerobic bacterium selectively enriched in the faecal and ...mucosal microbiota from patients with CRC, but its causative role and molecular mechanism in promoting tumorigenesis remain unestablished. We demonstrate that P. anaerobius adheres to the CRC mucosa and accelerates CRC development in Apc
mice. In vitro assays and transmission electron microscopy revealed that P. anaerobius selectively adheres to CRC cell lines (HT-29 and Caco-2) compared to normal colonic epithelial cells (NCM460). We identified a P. anaerobius surface protein, putative cell wall binding repeat 2 (PCWBR2), which directly interacts with colonic cell lines via α
/β
integrin, a receptor frequently overexpressed in human CRC tumours and cell lines. Interaction between PCWBR2 and integrin α
/β
induces the activation of the PI3K-Akt pathway in CRC cells via phospho-focal adhesion kinase, leading to increased cell proliferation and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. NF-κB in turn triggers a pro-inflammatory response as indicated by increased levels of cytokines, such as interleukin-10 and interferon-γ in the tumours of P. anaerobius-treated Apc
mice. Analyses of tumour-infiltrating immune cell populations in P. anaerobius-treated Apc
mice revealed significant expansion of myeloid-derived suppressor cells, tumour-associated macrophages and granulocytic tumour-associated neutrophils, which are associated with chronic inflammation and tumour progression. Blockade of integrin α
/β
by RGDS peptide, small interfering RNA or antibodies all impair P. anaerobius attachment and abolish P. anaerobius-mediated oncogenic response in vitro and in vivo. Collectively, we show that P. anaerobius drives CRC via a PCWBR2-integrin α
/β
-PI3K-Akt-NF-κB signalling axis and identify the PCWBR2-integrin α
/β
axis as a potential therapeutic target for CRC.
Summary
Lysine (Lys) is the first limiting essential amino acid in rice, a stable food for half of the world population. Efforts, including genetic engineering, have not achieved a desirable level of ...Lys in rice. Here, we genetically engineered rice to increase Lys levels by expressing bacterial lysine feedback‐insensitive aspartate kinase (AK) and dihydrodipicolinate synthase (DHPS) to enhance Lys biosynthesis; through RNA interference of rice lysine ketoglutaric acid reductase/saccharopine dehydropine dehydrogenase (LKR/SDH) to down‐regulate its catabolism; and by combined expression of AK and DHPS and interference of LKR/SDH to achieve both metabolic effects. In these transgenic plants, free Lys levels increased up to ~12‐fold in leaves and ~60‐fold in seeds, substantially greater than the 2.5‐fold increase in transgenic rice seeds reported by the only previous related study. To better understand the metabolic regulation of Lys accumulation in rice, metabolomic methods were employed to analyse the changes in metabolites of the Lys biosynthesis and catabolism pathways in leaves and seeds at different stages. Free Lys accumulation was mainly regulated by its biosynthesis in leaves and to a greater extent by catabolism in seeds. The transgenic plants did not show observable changes in plant growth and seed germination nor large changes in levels of asparagine (Asn) and glutamine (Gln) in leaves, which are the major amino acids transported into seeds. Although Lys was highly accumulated in leaves of certain transgenic lines, a corresponding higher Lys accumulation was not observed in seeds, suggesting that free Lys transport from leaves into seeds did not occur.
Rice is the main food source for about half of the world population. To meet the increasing demand of rice to feed the growing world population, the yield and quality must be increased. However world ...rice yields have been staying at plateau for many years by traditional breeding methods while lysine (Lys) content in rice remains below the minimum requirement of World Health Organization (WHO). Our lab has generated various transgenic C4 rice in an attempt to increase its photosynthetic rate, so as to increase its yield. At the same time, we have also generated rice with increased free Lys content, for nutrition enhancement. It has been proven that photosynthesis is the physiological basis of crop yield. More than 90% of crop biomass comes from photosynthetic products. Comparing with C3 crops, C4 plants with the higher photosynthetic rates are always associated with higher productivity. In our lab, transgenic rice overexpressing maize phosphoenolpyruvate carboxylase (PEPC)/pyruvate orthophosphate dikinase (PPDK) and maize NADP-malate dehydrogenase (MDH)/NADP-malic enzyme (ME) were produced with an attempt to increase its photosynthetic rate. However, our previous results showed that although transgenic rice with high expression of C4 genes at transcriptional, protein and enzyme activity levels, their grain productivity was not observed with such corresponding enhancement. Metabolomic methods were thus employed to study and compare the changes at metabolic level between transgenic and wild type (WT) leaves at four developing stages, with an aim to identify possible factors that may influence or limit the photosynthesis efficiency of the transgenic rice. Multivariate analysis suggested that changes at metabolite level differentiated mostly at early developmental stages and were “normalized” towards maturation. The metabolites contributed to the differences were those of sugar metabolism and tricarboxylic acid (TCA) cycle. Target analysis suggested that the efficiency of C4 enzymes varied, and PEPC was more efficient at early stages, as shown by enhanced TCA cycle activity and sucrose synthesis. The increased sucrose and some amino acids from TCA cycle at the early stage may make contributions to vegetative growth and enlarge the capacity of sink tissues. However, this contribution and enhancement could not be maintained at grain filling stage to provide continuous flow of nutrition from source to sink to increase the grain yield. Lys is the first limiting essential amino acid in rice. Efforts, thus far including genetic engineering, have not achieved a desirable level of Lys in rice. Here, we genetically engineered rice: to increase Lys levels by expressing bacterial Lys feedback-insensitive aspartate kinase (AK) and dihydrodipicolinate synthase (DHPS) to enhance Lys biosynthesis; through RNA interference of rice lysine ketoglutaric acid reductase/saccharopine dehydropine dehydrogenase (LKR/SDH) to downregulate its catabolism; and by combined expression of AK and DHPS and interference of LKR/SDH to achieve both metabolic effects. In these transgenic plants, free Lys levels increased up to ~60-fold in seeds and ~12-fold in leaves, substantially greater than the 2.5-fold increase in transgenic rice seeds by the only previous related study. To better understand the metabolic regulation of Lys accumulation in rice, metabolomic methods were employed to analyze the changes in metabolites in the Lys biosynthesis and catabolism pathways, in both leaves and seeds at different stages. Free Lys accumulation was mainly regulated by its V biosynthesis in leaves and to a greater extent by catabolism in seeds. The transgenic plants did not show observable changes in plant growth and seed germination nor marked changes in the levels of asparagine (Asn) and glutamine (Gln) in leaves, the major amino acids transported into seeds. Although Lys was highly accumulated in leaves of certain transgenic lines, a corresponding higher Lys accumulation was not observed in seeds, suggesting that free Lys transport from leaves into seeds likely did not occur.
Background Insulin-like growth factor binding protein-3 (IGFBP-3) is a multifunctional molecule which is closely related to cell growth, apoptosis, angiogenesis, metabolism and senescence. It ...combines with insulin-like growth factor-I (IGF-I) to form a complex (IGF-I/IGFBP-3) that can treat growth hormone insensitivity syndrome (GHIS) and reduce insulin requirement in patients with diabetes. IGFBP-3 alone has been shown to have anti-proliferation effect on numerous cancer cells. Methodology/Principal Findings We reported here an expression method to produce functional recombinant human IGFBP-3 (rhIGFBP-3) in transgenic rice grains. Protein sorting sequences, signal peptide and endoplasmic reticulum retention tetrapeptide (KDEL) were included in constructs for enhancing rhIGFBP-3 expression. Western blot analysis showed that only the constructs with signal peptide were successfully expressed in transgenic rice grains. Both rhIGFBP-3 proteins, with or without KDEL sorting sequence inhibited the growth of MCF-7 human breast cancer cells (65.76 plus or minus 1.72% vs 45.00 plus or minus 0.86%, p < 0.05; 50.84 plus or minus 1.97% vs 45.00 plus or minus 0.86%, p < 0.01 respectively) and HT-29 colon cancer cells (65.14 plus or minus 3.84% vs 18.01 plus or minus 13.81%, p < 0.05 and 54.7 plus or minus 9.44% vs 18.01 plus or minus 13.81%, p < 0.05 respectively) when compared with wild type rice. Conclusion/Significance These findings demonstrated the feasibility of producing biological active rhIGFBP-3 in rice using a transgenic approach, which will definitely encourage more research on the therapeutic use of hIGFBP-3 in future.
Congenital cataract (CC) is the primary cause of treatable childhood blindness worldwide. The establishment of reliable, epidemiological estimates is an essential first step towards management ...strategies. We undertook an initial systematic review and meta-analysis to estimate the prevalence and other epidemiological characteristics of CC. PubMed, Medline, Web of Science, Embase, and Cochrane Library were searched before January 2015. A meta-analysis with random-effects model based on a proportions approach was performed to determine the population-based prevalence of CC and to describe the data regarding the laterality, morphology, associated comorbidities and etiology. Heterogeneity was analyzed using the meta-regression method, and subgroup analyses were performed. 27 studies were selected from 2,610 references. The pooled prevalence estimate was 4.24 per 10,000 people, making it a rare disease based on WHO standards. Subgroup analyses revealed the highest CC prevalence in Asia, and an increasing prevalence trend through 2000. Other epidemiological characteristics showed CC tended to be bilateral, isolated, hereditary and in total/nuclear morphology. Huge heterogeneity was identified across most estimates (I(2) > 75%). Most of the variations could be explained by sample size, research period and age at diagnosis. The findings provide suggestions for etiology of CC, improvements in screening techniques and development of public health strategies.
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