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Supplementary Table S4 lists proteins that were found to bind SLFN11 after irradiation.

Glioblastoma (GBM) is an aggressive and incurable brain tumor in nearly all instances, whose disease progression is driven in part by the glioma stem cell (GSC) subpopulation. Here, we explored the effects of Schlafen family member 11 (SLFN11) in the molecular, cellular, and tumor biology of GBM. CRISPR/Cas9-mediated knockout of SLFN11 inhibited GBM cell proliferation and neurosphere growth and was associated with reduced expression of progenitor/stem cell marker genes, such as NES, SOX2, and CD44. Loss of SLFN11 stimulated expression of NFκB target genes, consistent with a negative regulatory role for SLFN11 on the NFκB pathway. Furthermore, our studies identify p21 as a direct transcriptional target of NFκB2 in GBM whose expression was stimulated by loss of SLFN11. Genetic disruption of SLFN11 blocked GBM growth and significantly extended survival in an orthotopic patient-derived xenograft model. Together, our results identify SLFN11 as a novel component of signaling pathways that contribute to GBM and GSC with implications for future diagnostic and therapeutic strategies.Significance:We identify a negative regulatory role for SLFN11 in noncanonical NFκB signaling that results in suppression of the cell-cycle inhibitor p21. We provide evidence that SLFN11 contributes to regulation of stem cell markers in GBM, promoting the malignant phenotype. In addition, SLFN11 targeting triggers p21 expression and antitumor responses. Our studies define a highly novel function for SLFN11 and identify it as a potential therapeutic target for GBM.

Fig. S1: Expression of SLFN family members after SLFN11 knockout. Fig. S2: Reduced 3-D invasion after SLFN11 knockout. Fig. S3: Expression of stem/progenitor markers after SLFN11 add-back. Table S1: Key resources table.

Glioblastoma (GBM) is an aggressive and incurable brain tumor in nearly all instances, whose disease progression is driven in part by the glioma stem cell (GSC) subpopulation. Here, we explored the effects of Schlafen family member 11 (SLFN11) in the molecular, cellular, and tumor biology of GBM. CRISPR/Cas9-mediated knockout of SLFN11 inhibited GBM cell proliferation and neurosphere growth and was associated with reduced expression of progenitor/stem cell marker genes, such as NES, SOX2, and CD44. Loss of SLFN11 stimulated expression of NFκB target genes, consistent with a negative regulatory role for SLFN11 on the NFκB pathway. Furthermore, our studies identify p21 as a direct transcriptional target of NFκB2 in GBM whose expression was stimulated by loss of SLFN11. Genetic disruption of SLFN11 blocked GBM growth and significantly extended survival in an orthotopic patient-derived xenograft model. Together, our results identify SLFN11 as a novel component of signaling pathways that contribute to GBM and GSC with implications for future diagnostic and therapeutic strategies. Significance: We identify a negative regulatory role for SLFN11 in noncanonical NFκB signaling that results in suppression of the cell-cycle inhibitor p21. We provide evidence that SLFN11 contributes to regulation of stem cell markers in GBM, promoting the malignant phenotype. In addition, SLFN11 targeting triggers p21 expression and antitumor responses. Our studies define a highly novel function for SLFN11 and identify it as a potential therapeutic target for GBM.

The objective was to compare the impact of black lentil (BL) water and delphinidin 3-O-(2-O-β-d-glucopyranosyl-α-l-arabinopyranoside) (D3G)-rich lentil extracts on tumor development, inflammation and immune response in an azoxymethane (AOM)/dextran sodium sulfate (DSS) model. C57BL/6 mice were randomly separated into four groups: healthy control (n = 6), AOM/DSS control (n = 14), AOM/DSS + BL (600 mg/kg body wt, n = 12) and AOM/DSS + D3G (41 mg/kg body wt, equivalent to D3G concentration in BL, n = 12). Mice were given treatments for 11 weeks using a voluntary jelly administration. AOM/DSS + BL presented a lower (P < 0.05) disease activity index, throughout and at the end (2.4) compared with AOM/DSS (6.3). AOM/DSS + BL mice had an average of 7.8 neoplasms versus 12.8 for the AOM/DSS (P < 0.05). Proinflammatory cytokines were downregulated in the colon mucosa: interleukin (IL)-1β (−77.5%, −70.7%) and IL-6 (−44.4%, −44.9%) by AOM/DSS + BL and AOM/DSS + D3G, respectively, compared with AOM/DSS. IL-6 protein expression was decreased by BL in plasma (−72.6%) and gene expression in colon polyps (fold change: −4.0) compared with AOM/DSS. AOM/DSS + D3G non-polyp tissue gene expression clustered with the healthy control tissue with only four genes modified (secreted phosphoprotein 1 and CXC motif chemokine ligands 2, 5 and 10). AOM/DSS + BL downregulated programmed death-ligand 1 protein expression in colon tissue (−54.7%) and gene expression by 2.8-fold compared with the AOM/DSS control. In fecal samples, gallic and protocatechuic acids and epicatechin were found, and concentration of most amino acids was lower and unsaturated fatty acids were higher for AOM/DSS + BL and AOM/DSS + D3G. BL and D3G-rich extracts showed anti-inflammatory and proimmune response effects while BL additionally prevented growth of neoplasia.

Many factors complicate therapeutic strategies for glioblastoma (GBM), including the existence of the blood brain barrier and a heterogenous population of difficult to treat glioma stem cells. Innovative strategies targeting novel pathways alone or in combination are needed for sustainable therapeutic improvements. The MAPK pathway has been implicated in many cancers. MAPK interacting kinases (MNK1 and MNK2) are downstream of MAPKs and phosphorylate the eukaryotic translation initiation factor 4E (eIF4E), a protein involved in translation of oncogenic mRNAs. We have previously established pharmacological MNK inhibition as a promising strategy for GBM. However, most currently available MNK inhibitors lack specificity and exhibit off-target effects. We developed novel selective MNK inhibitors that show MNK inhibition specificity in GBM established cell lines as well as patient-derived cell lines propagated under stem cell permissive conditions as 3-D neurospheres. MNK inhibitors reduced cell viability and neurosphere growth. Our previous work with MNK inhibitors showed involvement in negative feedback loops activated with treatment of other pharmacological agents, so we conducted a high-throughput screening to identify potential targets for combination treatment. One of the top hits was a DNA methyltransferase (DNMT) inhibitor that enhanced MNK inhibitor antineoplastic effects in GBM cells. Dual MNK and DNMT inhibition synergistically reduced neurosphere growth in 3-D glioma stem-like cells. The combination promoted apoptosis in the mesenchymal glioma stem-like cells as shown through flow cytometry and increased expression of cleaved PARP, cleaved caspase 3, and Bax. Also, DNMT targeting enhanced the viability reduction effects of siRNA mediated MNK1 knockdown in GBM cells. This combination of our novel MNK inhibitor with DNMT inhibition elicited antineoplastic benefits in both 2-D cultures and 3-D glioma stem cell-like populations, demonstrating a potential novel therapeutic strategy in GBM. Citation Format: Candice Mazewski, Frank Eckerdt, Aneta Baran, Mariafausta Fischietti, Purav P. Vagadia, Ricardo E. Perez, Charles D. James, Gary E. Schiltz, Leonidas C. Platanias. DNMT targeting enhances vulnerability of glioblastoma cells to MNK inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3281.

OBJECTIVES: The objective was to compare the impact of black lentil water extract (BL) and delphinidin 3-O-(2-O-β-d-glucopyranosyl-α-l-arabinopyranoside) (D3G)-rich lentil extract on tumor development and inflammation in an azoxymethane (AOM)/dextran sodium sulfate (DSS) model. METHODS: C57BL/6 mice were randomly separated into four groups: healthy control (n = 6), AOM/DSS control (n = 14), AOM/DSS + BL (600 mg/kg body weight, n = 12), and AOM/DSS + D3G (41 mg/kg body weight, equivalent to D3G concentration in BL, n = 12). Mice were given treatments for 11 weeks using a voluntary oral jelly administration. Fecal samples were collected three times: after one week of treatments prior to the first AOM injection, after the first (of three) DSS cycle, and at the time of euthanasia. Secretory leukoprotease inhibitor (SLPI) expression was evaluated by qPCR, calprotectin by ELISA and fecal metabolite profiles by Agilent GC-MS system. RESULTS: AOM/DSS + BL presented a lower (p

The objective was to compare the anti-proliferative effect of anthocyanin-rich plant extracts on human colon cancer cells and determine their mechanism of action. Eleven extracts were tested: red (RG) and purple grape, purple sweet potato, purple carrot, black and purple bean, black lentil (BL), black peanut, sorghum (SH), black rice, and blue wheat. HCT-116 and HT-29 inhibition correlated with total phenolics (r=0.87 and 0.77, respectively), delphinidin-3-O-glucoside concentration with HT-29 inhibition (r=0.69). The concentration inhibition fifty (IC50) for BL, SH, RG on HT-29 and HCT-116 cell proliferation ranged 0.9-2.0mg/mL. Extracts decreased expression of anti-apoptotic proteins (survivin, cIAP-2, XIAP), induced apoptosis, and arrested cells in G1. Anthocyanins exhibited tyrosine kinase inhibitory potential in silico and biochemically; cyanidin-3-O-glucoside had one of the highest binding affinities with all kinases, especially ABL1 (-8.5kcal/mol). Cyanidin-3-O-glucoside and delphinidin-3-O-glucoside inhibited EGFR (IC50=0.10 and 2.37µM, respectively). Cyanidin-3-O-glucoside was the most potent anthocyanin on kinase inhibition.

The objective was to assess anti-progression and stimulatory immune response effects among anthocyanins (ANC) and their metabolites on human colorectal cancer cells in vitro and in silico. Pure phenolics including delphinidin-3-O-glucoside (D3G) and its metabolites, delphinidin (DC) and gallic acid (GA), were tested alone or in combination, on HCT-116 and HT-29 human colorectal cancer cells (100–600 µg/mL). HCT-116 and HT-29 50% inhibition concentrations (µg/mL) were 396 ± 23 and 329 ± 17 for D3G; 242 ± 16 and >600 for DC; and 154 ± 5 and 81 ± 5 for GA, respectively. Using molecular docking, cyanidin-3-O-glucoside (C3G) showed the highest potential to inhibit immune checkpoints: programmed cell death protein-1 (PD-1) (−6.8 kcal/mol) and programmed death-ligand-1 (PD-L1) (−9.6 kcal/mol). C3G, D3G, DC, GA, and D3G-rich extracts decreased PD-L1 protein expression in HCT-116 cells. C3G decreased PD-L1 fluorescence intensity by 39%. ANC decreased PD-1 expression in peripheral blood mononuclear cells in monoculture by 41% and 55%, and co-culture with HCT-116 and HT-29 cells by 39% and 26% (C3G) and 50% and 51% (D3G), respectively. D3G and C3G, abundant in plant foods, showed potential for binding with and inhibiting immune checkpoints, PD-1 and PD-L1, which can activate immune response in the tumor microenvironment and induce cancer cell death.

Diet and nutrition are undeniably two factors that have a major impact on the prevention, progression, and treatment of various cancers. In this review, we will discuss how bioactives from diet and nutritional status affect each of the hallmarks of cancer. We will present recent research and discuss using diet and nutrition as a means to prevent and treat cancer.