Magnaporthe oryzae infection triggers rice resistance to brown planthopper through the influence of jasmonic acid on the flavonoid biosynthesis pathway.

In agroecosystems, plants are constantly exposed to attack from diverse herbivorous insects and microbes, and infestation with one species may change the plant defense response to other species. In our investigation of the relationships among rice plants, the brown planthopper Nilaparvata lugens (Stål) and the rice blast fungus Magnaporthe oryzae, we observed a significant increase in the resistance of rice treated with rice blast to N. lugens, as evidenced by improved plant survival rates in a small population resistance study. Subsequent transcriptome data analysis revealed that the rice blast fungus can induce the expression of genes in the jasmonic acid (JA) and flavonoid pathways. Similar to the flavonoid pathway, the JA pathway also contains 2 types of genes that exhibit similar and opposite trends in response to N. lugens and rice blast. Among these genes, the osjaz1 mutant and the osmyc2 mutant were phenotypically confirmed to positively and negatively regulate rice resistance to N. lugens and rice blast, respectively. Subsequent mass spectrometry and quantification experiments showed that the exogenous application of methyl jasmonate (MeJA) can induce the accumulation of eriodictyol, naringenin and quercetin, as well as the expression of OsF3H, Os4CL5 and OsCHI in the flavonoid pathway. This suggests a close connection between the JA pathway and the flavonoid pathway. However, OsF3'H, which negatively regulates rice resistance to N. lugens and rice blast, did not show increased expression. Phenotypic and molecular experiments confirmed that OsMYC2 can bind to and inhibit the expression of OsF3'H, thus revealing the mechanism of rice resistance to N. lugens after treatment with rice blast. These findings will deepen our understanding of the interactions among rice, N. lugens and rice blast.

Acylcarnitines promote gallbladder cancer metastasis through lncBCL2L11-THOC5-JNK axis.

BACKGROUND: The progression of gallbladder cancer (GBC) is accompanied by abnormal fatty acid ß-oxidation (FAO) metabolism. Different types of lipids perform various biological functions. This study aimed to determine the role of acyl carnitines in the molecular mechanisms of GBC progression. METHODS: Distribution of lipids in GBC was described by LC-MS-based lipidomics. Cellular localization, expression level and full-length of lncBCL2L11 were detected using fluorescence in situ hybridization (FISH) assays, subcellular fractionation assay and 5' and 3' rapid amplification of the cDNA ends (RACE), respectively. In vitro and in vivo experiments were used to verify the biological function of lncBCL2L11 in GBC cells. Methylated RNA Immunoprecipitation (MeRIP) was performed to detect the methylation levels of lncBCL2L11. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were used to identify lncBCL2L11 interacting proteins. Co-Immunoprecipitation (Co-IP) and Western blot assay were performed to validate the regulatory mechanism of lncBCL2L11 and THO complex. RESULTS: Acylcarnitines were significantly up-regulated in GBC tissues. High serum triglycerides correlated to decreased survival in GBC patients and promoted tumor migration. LncBCL2L11 was identified in the joint analysis of highly metastatic cells and RNA sequencing data. LncBCl2L11 prevented the binding of THOC6 and THOC5 and causes the degradation of THOC5, thus promoting the accumulation of acylcarnitines in GBC cells, leading to the malignant progression of cancer cells. In addition, highly expressed acylcarnitines stabilized the expression of lncBCL2L11 through N6-methyladenosine methylation (m6A), forming a positive feedback regulation in tumor dissemination. CONCLUSIONS: LncBCL2L11 is involved in gallbladder cancer metastasis through FAO metabolism. High lipid intake is associated with poor prognosis of GBC. Therefore, targeting lncBCL2L11 and its pathway-related proteins or reducing lipid intake may be significant for the treatment of GBC patients.

Community ecological succession of endophytic fungi associates with medicinal compound accumulation in Sophora alopecuroides.

Endophytic fungi of medicinal plants are symbiotic with the host and play an important role in determining metabolites. To understand the relationship between the accumulation of Sophora alopecuroides' medicinal bioactive compounds and the ecological succession of endophytic fungi, here we collected samples from S. alopecuroides at four developmental stages (adult, flowering, podding, and mature) and different organs (roots, stems, leaves, and seeds) at the mature stage. We then used high-performance liquid chromatography-mass spectrometry and high-throughput sequencing on the internal transcribed spacer region to identify the medicinal compounds and endophytic fungal communities in each sample. The endophytic fungal community characteristics and accumulation of medicinally bioactive compounds of S. alopecuroides varied with the host's developmental stages and organs, with the highest total alkaloids content of 111.9 mg/g at the mature stage. Membership analysis and network connection analysis showed a total of 15 core endophytic fungi in different developmental stages and 16 core endophytic fungi in different organs at the mature stage. The unclassified Ascomycota, Aspergillus, and Alternaria were significantly and positively correlated with the medicinal compounds of S. alopecuroides at the mature stage (r > 0.6 or r < -0.6; P < 0.05). In this study, we identified key endophytic fungal resources that affect the content of medicinally bioactive compounds in S. alopecuroides. This discovery could lay the foundation for enhancing the yield of medicinally bioactive compounds in S. alopecuroides and the development and application of functional endophytic fungi.IMPORTANCESophora alopecuroides is a traditional Chinese herbal medicine. The major medicinal chemicals are considered to be quinolizidine alkaloids. Quinolizidine alkaloids have been widely used for the treatment of tumors, dysentery, and enteritis. Previous studies have found that endophytic fungi in S. alopecuroides can promote the accumulation of host quinolizidine alkaloids. However, the relationship between the accumulation of S. alopecuroides' medicinal bioactive compounds and the ecological succession of endophytic fungi remains unclear. In this study, we screened the key endophytic fungal resources affecting the content of medicinally bioactive compounds and laid the foundation for subsequent research on the mechanism by which endophytic fungi promote the accumulation of medicinally bioactive compounds in S. alopecuroides.

Transcriptional response of wolfberry to infestation with the endophytic Fusarium nematophilum strain NQ8GII4.

Fusarium nematophilum NQ8GII4 is an endophytic fungus isolated from the root of healthy wolfberry (Lycium barbarum). Previous studies have reported that NQ8GII4 could dwell in wolfberry roots and enhance the defense responses in wolfberry against root rot, which is caused by F. oxysporum. To further elucidate the molecular mechanism of wolfberry disease resistance induced by NQ8GII4, in the present study, we adopted RNA sequencing analysis to profile the transcriptome of wolfberry response to NQ8GII4 infestation over a time course of 3 and 7 days post-inoculation (dpi). Gene ontology (GO) enrichment analysis revealed that DEGs were enriched related to biological regulation, response to stimulus, signaling, detoxification, immune system process, transporter activity, electron carrier activity, transcription factor activity, nucleic acid binding transcription factor, and antioxidant activity. Through Kyoto encyclopedia of genes and genomes (KEGG) analysis, it was found that many of these DEGs were enriched in pathways related to plant-pathogen interactions, hormone signal transduction, and phenylpropanoid biosynthesis pathway in wolfberry. This suggests that innate immunity, phytohormone signaling, and numerous phenylpropanoid compounds, which comprise a complex defense network in wolfberry. Chloroplast 50S ribosomal proteins (50S RP) were consistently located at the core position of the response in wolfberry following infestation with NQ8GII4 analyzed by protein-protein interaction (PPI) network. This study elucidated the molecular mechanism underlying the interaction between NQ8GII4 and wolfberry, clarified the wolfberry immune response network to endophytic fungi infestation, identified candidate resistance genes in wolfberry, and provided a fundamental date for subsequent work.

GNL3L promotes autophagy via regulating AMPK signaling in esophageal cancer cells.

Guanine nucleotide-binding protein-like 3-like (GNL3L), a conserved GTP-binding nucleolar protein, participates in regulating cell proliferation, and associates with tumorigenesis and poor prognosis in several kind of cancers. However, the role of GNL3L in modulating autophagy remains unclear. Here, we verified that GNL3L was higher expressed in esophageal cancer (ESCA) biopsies than that in the corresponding normal biopsies by a human ESCA tissue array. Utilizing immunoblotting and real-time PCR assays, we analyzed the expression of GNL3L in several ESCA cell lines, and it was highly expressed in KYSE410 cells and rarely expressed in KYSE150 cells, respectively. GNL3L overexpression promoted cell viability and cell proliferation in KYSE150 cells. On the contrary, silencing of GNL3L resulted in opposite phenotypes in KYSE410 cells. Furthermore, GNL3L level correlated with autophagic flux and influenced the levels of autophagy core proteins. Meanwhile, GNL3L also affected the AMPK signaling pathway, which is a pivotal signaling pathway for autophagy regulation. In the GNL3L-silenced cells, the AMPK agonist AICAR partly rescued the autophagic flux. Inversely, both pharmacologically and genetically deprivation of AMPK attenuated the autophagic flux induced by GNL3L overexpression. Moreover, AMPK activity alteration influenced the effect of GNL3L in regulating cell proliferation. Collectively, these findings suggest that GNL3L positively regulates cell proliferation and autophagy in ESCA cells via regulating the AMPK signaling, making itself a promising therapeutic target for ESCA.

A Novel LSTM-Based Machine Learning Model for Predicting the Activity of Food Protein-Derived Antihypertensive Peptides.

Food protein-derived antihypertensive peptides are a representative type of bioactive peptides. Several models based on partial least squares regression have been constructed to delineate the relationship between the structure and activity of the peptides. Machine-learning-based models have been applied in broad areas, which also indicates their potential to be incorporated into the field of bioactive peptides. In this study, a long short-term memory (LSTM) algorithm-based deep learning model was constructed, which could predict the IC50 value of the peptide in inhibiting ACE activity. In addition to the test dataset, the model was also validated using randomly synthesized peptides. The LSTM-based model constructed in this study provides an efficient and simplified method for screening antihypertensive peptides from food proteins.

Let's be fair. What about an AI editor?

Much of the current attention on artificial intelligence (AI)-based natural language processing (NLP) systems has focused on research ethics and integrity but neglects their roles in the editorial and peer-reviewing process. We argue that the academic community needs to develop and apply a consistent end-to-end policy on the ethics and integrity of NLP in academic publishing: standards such as drafting requirements and disclosure criteria imposed on potential contributors should be consistently applied to the editorial and peer review process in academic publications.

Phylogenomics and plastome evolution of Indigofera (Fabaceae).

Introduction: Indigofera L. is the third largest genus in Fabaceae and includes economically important species that are used for indigo dye-producing, medicinal, ornamental, and soil and water conservation. The genus is taxonomically difficult due to the high level of overlap in morphological characters of interspecies, fewer reliability states for classification, and extensive adaptive evolution. Previous characteristic-based taxonomy and nuclear ITS-based phylogenies have contributed to our understanding of Indigofera taxonomy and evolution. However, the lack of chloroplast genomic resources limits our comprehensive understanding of the phylogenetic relationships and evolutionary processes of Indigofera. Methods: Here, we newly assembled 18 chloroplast genomes of Indigofera. We performed a series of analyses of genome structure, nucleotide diversity, phylogenetic analysis, species pairwise Ka/Ks ratios, and positive selection analysis by combining with allied species in Papilionoideae. Results and discussion: The chloroplast genomes of Indigofera exhibited highly conserved structures and ranged in size from 157,918 to 160,040 bp, containing 83 protein-coding genes, 37 tRNA genes, and eight rRNA genes. Thirteen highly variable regions were identified, of which trnK-rbcL, ndhF-trnL, and ycf1 were considered as candidate DNA barcodes for species identification of Indigofera. Phylogenetic analysis using maximum likelihood (ML) and Bayesian inference (BI) methods based on complete chloroplast genome and protein-coding genes (PCGs) generated a well-resolved phylogeny of Indigofera and allied species. Indigofera monophyly was strongly supported, and four monophyletic lineages (i.e., the Pantropical, East Asian, Tethyan, and Palaeotropical clades) were resolved within the genus. The species pairwise Ka/Ks ratios showed values lower than 1, and 13 genes with significant posterior probabilities for codon sites were identified in the positive selection analysis using the branch-site model, eight of which were associated with photosynthesis. Positive selection of accD suggested that Indigofera species have experienced adaptive evolution to selection pressures imposed by their herbivores and pathogens. Our study provided insight into the structural variation of chloroplast genomes, phylogenetic relationships, and adaptive evolution in Indigofera. These results will facilitate future studies on species identification, interspecific and intraspecific delimitation, adaptive evolution, and the phylogenetic relationships of the genus Indigofera.

COPS3 inhibition promotes cell proliferation blockage and anoikis via regulating PFKFB3 in osteosarcoma cancer cells.

As a key component of the COP9 signalosome complex, which participates in a variety of physiological processes, COPS3 is intimately related to multiple cancers. It promotes cell proliferation, progression and metastasis in several cancer cells. However, whether COPS3 participates in regulating anoikis, a specific kind of apoptosis and functions as an essential modulator of cell metastasis, has not yet been studied. Here, we found COPS3 is highly expressed in several cancers especially in osteosarcoma (OS). Overexpression of COPS3 promoted cell proliferation, cell viability and migration/invasion in both control cells and oxaliplatin (Oxa) treated cells. On the contrary, knockdown of COPS3 further enhanced the cytotoxicity of Oxa. Utilizing bioinformatics analysis, we found that COPS3 was higher expressed in the metastatic group, and associated with the extra-cellular matrix (ECM) receptor interaction pathway, which involve in regulating anoikis. In an anoikis model, COPS3 expression varied and genetic modification of COPS3 influenced the cell death enhanced by Oxa. PFKFB3, an essential modulator of glycolysis, was found to interact with COPS3. Inhibition of PFKFB3 promoted apoptosis and anoikis enhanced by Oxa, and COPS3 overexpression failed to rescue this cell death. On the contrary, in the COPS3 knockdown cells, overexpression of PFKFB3 recovered the anoikis resistance, indicating COPS3 function upstream of PFKFB3. In summary, our results elucidated that COPS3 modulated anoikis via affecting PFKFB3 in OS cancer cells.

Long-term exposure to genistein inhibits the proliferation of gallbladder cancer by downregulating the MCM complex.

Soy isoflavones are natural tyrosine kinase inhibitors closely associated with decreased morbidity and mortality of various tumors. The activation of tyrosine kinases such as ERBB2 is the mechanism by which cholecystitis transforms into gallbladder cancer (GBC), therefore, it is important to investigate the relationship between long-term exposure to soy isoflavones and the occurrence and progression of GBC. This case-control study (n = 85 pairs) found that the high level of plasma soy isoflavone-genistein (GEN) was associated with a lower risk of gallbladder cancer (≥326.00 ng/mL compared to ≤19.30 ng/mL, crude odds ratio 0.15, 95% CI 0.04-0.59; P for trend = 0.016), and that the level of GEN exposure negatively correlated with Ki67 expression in GBC tissue (n = 85). Consistent with these results, the proliferation of GBC cells was inhibited in the long-term exposure models of GEN in vitro and in vivo. The long-term exposure to GEN reduced the tyrosine kinase activity of ERBB2 and impaired the function of the PTK6-AKT-GSK3ß axis, leading to downregulation of the MCM complex in GBC cells. In summary, long-term exposure to GEN associated with soy products intake might play a certain role in preventing GBC and even inhibiting the proliferation of GBC cells.

Idarubicin combats abiraterone and enzalutamide resistance in prostate cells via targeting XPA protein.

Although second-generation therapies like abiraterone (ABI) and enzalutamide (ENZ) benefit patients with castration-resistant prostate cancer (CRPC), drug resistance frequently occurs, eventually resulting in therapy failure. In this study, we used two libraries, FDA-approved drug library and CRISP/Cas9 knockout (GeCKO) library to screen for drugs that overcome treatment resistance and to identify the potential drug-resistant genes involved in treatment resistance. Our screening results showed that the DNA-damaging agent idarubicin (IDA) overcame abiraterone and enzalutamide resistance in prostate cancer cells. IDA treatment inhibited the DNA repair protein XPA expression in a transcription-independent manner. Consistently, XPA knockout sensitized prostate cancer cells to abiraterone and enzalutamide treatment. In conclusion, IDA combats abiraterone and enzalutamide resistance by reducing XPA protein level in prostate cancer.

The Endophytic Fungi Diversity, Community Structure, and Ecological Function Prediction of Sophora alopecuroides in Ningxia, China.

Sophora alopecuroides L. has great medicinal and ecological value in northwestern China. The host and its microbiota are mutually symbiotic, collectively forming a holobiont, conferring beneficial effects to the plant. However, the analysis of diversity, mycobiota composition, and the ecological function of endophytic fungi in the holobiont of S. alopecuroides is relatively lacking. In this article, the fungal community profiling of roots, stems, leaves, and seeds of S. alopecuroides (at the fruit maturity stage) from Huamachi and Baofeng in Ningxia, China were investigated based on the ITS1 region, using high-throughput sequencing technology. As a result, a total of 751 operational taxonomic units (OTUs) were obtained and further classified into 9 phyla, 27 classes, 66 orders, 141 families, 245 genera, and 340 species. The roots had the highest fungal richness and diversity, while the stems had the highest evenness and pedigree diversity. There also was a significant difference in the richness of the endophytic fungal community between root and seed (p < 0.05). The organ was the main factor affecting the community structure of endophytic fungi in S. alopecuroides. The genera of unclassified Ascomycota, Tricholoma, Apiotrichum, Alternaria, and Aspergillus made up the vast majority of relative abundance, which were common in all four organs as well. The dominant and endemic genera and biomarkers of endophytic fungi in four organs of S. alopecuroides were different and exhibited organ specificity or tissue preference. The endophytic fungi of S. alopecuroides were mainly divided into 15 ecological function groups, among which saprotroph was absolutely dominant, followed by mixotrophic and pathotroph, and the symbiotroph was the least. With this study, we revealed the diversity and community structure and predicted the ecological function of the endophytic fungi of S. alopecuroides, which provided a theoretical reference for the further development and utilization of the endophytic fungi resources of S. alopecuroides.

Correlation in endophytic fungi community diversity and bioactive compounds of Sophora alopecuroides.

Sophora alopecuroides L. is a traditional Chinese medicine used for the treatment of several different disease states including bacillary dysentery and enteritis. But importantly, it also plays a role as an anti-tumor agent. That said, little is known about the role endophytes play regarding the clinically bioactive metabolites in S. alopecuroides. In order to explore the effects of endophytic fungi on the accumulation, quality, and correlation in the content of the medicinal compounds, the structural diversity of endophytic fungi in S. alopecuroides was analyzed. The relationship between endophytes and quinolizidine alkaloids (QAs), housed within the seeds of S. alopecuroides, which were interpreted based on established methods of high-throughput sequencing and high-performance liquid chromatography. A total of 1,034,418 effective sequence reads and 257 operational taxonomic units (OTUs) were obtained from 33 samples which were sourced from 11 different sampling sites and further classified into 9 phyla, 20 classes, 45 orders, 85 families, and 118 genera. Ascomycota was found to be the dominant phylum of endophytic fungi in S. alopecuroides, with a relative abundance ranging from 60.85 to 98.30%. Alternaria, Cladosporium, Filobasidium, and an unidentified Ascomycota were the core-shared endophytes, accounting for 49.96, 27.12, 14.83, and 7.88%, respectively. Correlation analysis showed that the Simpson's diversity index of endophytic fungal community in S. alopecuroides was significantly positively correlated with the Oxymatrine (OMA) content in different areas, while the Chao and Shannoneven indexes were significantly negatively correlated with OMA. The endophytic fungi of Alternaria were positively correlated with the content of OMA, Oxysophocarpine (OSC), and total QAs. This study has mastered the endophytic fungi resources of S. alopecuroides, explored potential functional endophytic fungi, and provided a scientific basis for using biological fertilization strategies to improve the quality of S. alopecuroides.

The role of PFKFB3 in maintaining colorectal cancer cell proliferation and stemness.

Since generally confronting with the hypoxic and stressful microenvironment, cancer cells alter their glucose metabolism pattern to glycolysis to sustain the continuous proliferation and vigorous biological activities. Bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) isoform 3 (PFKFB3) functions as an effectively modulator of glycolysis and also participates in regulating angiogenesis, cell death and cell stemness. Meanwhile, PFKFB3 is highly expressed in a variety of cancer cells, and can be activated by several regulatory factors, such as hypoxia, inflammation and cellular signals. In colorectal cancer (CRC) cells, PFKFB3 not only has the property of high expression, but also probably relate to inflammation-cancer transformation. Recent studies indicate that PFKFB3 is involved in chemoradiotherapy resistance as well, such as breast cancer, endometrial cancer and CRC. Cancer stem cells (CSCs) are self-renewable cell types that contribute to oncogenesis, metastasis and relapse. Several studies indicate that CSCs utilize glycolysis to fulfill their energetic and biosynthetic demands in order to maintain rapid proliferation and adapt to the tumor microenvironment changes. In addition, elevated PFKFB3 has been reported to correlate with self-renewal and metastatic outgrowth in numerous kinds of CSCs. This review summarizes our current understanding of PFKFB3 roles in modulating cancer metabolism to maintain cell proliferation and stemness, and discusses its feasibility as a potential target for the discovery of antineoplastic agents, especially in CRC.

AICAR enhances the cytotoxicity of PFKFB3 inhibitor in an AMPK signaling-independent manner in colorectal cancer cells.

Numerous studies have shown that 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), a pivotal enzyme in modulating glycolysis, plays vital roles in various physiological processes. PFKFB3 activity could be regulated by several factors, such as hypoxia and AMPK signaling; however, it could also function as upstream of AMPK signaling. Here, we showed that PFKFB3 inhibitor PFK-15 induced cell viability loss and apoptosis. Deprivation of PFKFB3 inhibited autophagy, while enhanced the ubiquitin-proteasome degradation pathway. Furthermore, PFK-15 reduced both the AMPK and AKT-mTORC1 signaling pathways, as the attenuated phosphorylation level of kinases themselves and their substrates. The addition of AICAR rescued the AMPK activity and autophagy, but enhanced PFK-15-induced cell viability loss. In fact, AICAR promoted the cytotoxicity of PFK-15 even in the AMPKα1/2-silenced cells, indicating AICAR might function in an AMPK-independent manner. Nevertheless, AICAR further reduced the AKT-mTORC1 activity down-regulated by PFK-15. Moreover, it failed to enhance PFK-15's cytotoxicity in the AKT1/2-silenced cells, indicating AKT-mTORC1 participated during these processes. Collectively, the presented data demonstrated that PFK-15 inhibited cell viability, AMPK, and AKT-mTORC1 signaling, and AICAR probably enhanced the cell viability loss aroused by PFK-15 in an AKT-dependent and AMPK-independent manner, thereby revealing a more intimate relationship among PFKFB3, AMPK, and AKT-mTORC1 signaling pathways.

Bortezomib potentiates antitumor activity of mitoxantrone through dampening Wnt/ß-catenin signal pathway in prostate cancer cells.

BACKGROUND: Bortezomib (BZM), alone or in combination with other chemotherapies, has displayed strong anticancer effects in several cancers. The efficacy of the combination of BZM and mitoxantrone (MTX) in treating prostate cancer remains unknown. METHODS: Anticancer effects of combination of BZM and MTX were determined by apoptosis and proliferation assay in vivo and in vitro. Expression of ß-Catenin and its target genes were characterized by western blot and Real-time PCR. RESULTS: BZM significantly enhanced MTX-induced antiproliferation in vivo and in vitro. Mice administered a combination of BZM and MTX displayed attenuated tumor growth and prolonged survival. BZM significantly attenuated MTX-induced apoptosis. Moreover, the combination of BZM and MTX contributed to inhibition of the Wnt/ß-Catenin signaling pathway compared to monotherapy. CONCLUSIONS: This study demonstrates that BZM enhances MTX-induced anti-tumor effects by inhibiting the Wnt/ß-Catenin signaling pathway in prostate cancer cells.

Alternol triggers immunogenic cell death via reactive oxygen species generation.

Alternol is a naturally occurring compound that exerts antitumor activity in several cancers. However, whether Alternol induces antitumor immune response remains unknown. In this study, we investigated whether Alternol induced immunogenic cell death (ICD) in prostate cancer cells. Alternol triggered ICD in prostate cancer cells, as evidenced by the release of damage-associated molecular patterns (DAMPs) (i.e., calreticulin, CALR; high mobility group protein B1, HMGB1; and adenosine triphosphate, ATP) and pro-inflammatory cytokine (i.e., interleukin [IL]-1α, IL-1ß, IL-6, and IL-8) expression. Alternol facilitated tumor-associated antigen uptake and cross-presentation, CD8 + T-cell priming, and T-cell infiltration in tumor-draining lymph nodes (LNs) and tumors. The presence of Alternol fostered antitumor immune response in vivo, resulting in delayed tumor growth and prolonged survival. Moreover, inhibition of reactive oxygen species (ROS) generation blocked Alternol-induced upregulation of pre-inflammation cytokines, endoplasmic reticulum (ER) stress, and consequent antitumor immune response. Overall, our data indicate that Alternol triggers ICD in prostate cancer cells, which is mediated by ROS generation.

Erratum: CCL16 maintains stem cell-like properties in breast cancer by activating CCR2/GSK3ß/ß-catenin/OCT4 axis: Erratum.

[This corrects the article DOI: 10.7150/thno.51000.].

Necroptosis pathway blockage attenuates PFKFB3 inhibitor-induced cell viability loss and genome instability in colorectal cancer cells.

Cancer cells prone to utilize aerobic glycolysis other than oxidative phosphorylation to sustain its continuous cell activity in the stress microenvironment. Meanwhile, cancer cells generally suffer from genome instability, and both radiotherapy and chemotherapy may arouse DNA strand break, a common phenotype of genome instability. Glycolytic enzyme PFKFB3 (6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3), plays essential roles in variety physiology and pathology processes, and generally maintain high level in cancer cells. Although this protein has been reported to involve in genome instability, its role remains unclear and controversial. Here, we showed that PFK-15, a PFKFB3 inhibitor, obviously induced apoptosis, cell viability loss, and inhibited cell proliferation/migration. Besides, PFK-15 was also found to induce necroptosis, as it not only up-regulated the phosphorylated RIP1, RIP3 and MLKL, but also enhanced the interaction between RIP3 and RIP1/MLKL, all of which are characterization of necroptosis induction. Both genetically and pharmacologically deprivation of necroptosis attenuated the cytotoxic effect of PFK-15. Besides, PFK-15 increased the γ-H2AX level and micronuclei formation, markers for genome instability, and inhibition of necroptosis attenuated these phenotypes. Collectively, the presented data demonstrated that PFK-15 induced genome instability and necroptosis, and deprivation of necroptosis attenuated cytotoxicity and genotoxicity of PFK-15 in colorectal cancer cells, thereby revealing a more intimate relationship among PFKFB3, necroptosis and genome instability.