Targeting PGM3 as a Novel Therapeutic Strategy in KRAS/LKB1 Co-Mutant Lung Cancer
<p>GFPT2 inhibition selectively reduces glycosylation of KL co-mutant NSCLC cells. (<b>A</b>) Schematic of the HBP, including azaserine, the GFPT inhibitor. Metabolites are in black and enzymes are in red. Metabolites in the glycosylation pathway are shaded in lilac and those in O-GlcNAcylation are shaded in light blue. F6P, fructose-6-phosphate; Gln, glutamine. (<b>B</b>) GFPT2 and LKB1 expression levels were measured in H2122 (<b>left</b>) and H460 (<b>right</b>) KL co-mutant cells depleted of GFPT2 using endoribonuclease-prepared siRNA (esi<span class="html-italic">GFPT2</span>). Actin was used as the loading control. (<b>C</b>) Schematic for cell-surface <span class="html-italic">Sambucus nigra</span> (SNA), <span class="html-italic">Lycopersicon esculentum</span> (LEA), phytohemagglutinin-L (L-PHA) lectins, and corresponding glycan structures, where each lectin interacts. Symbol nomenclature for glycans is shown. (<b>D</b>) Cell surface L-PHA lectin binding was measured by flow cytometry in empty vector (EV)- and LKB1-expressing H460 (<b>left</b>) and H2122 (<b>right</b>) KL co-mutant cells depleted of GFPT2 by esi<span class="html-italic">GFPT2</span>. (<b>E</b>) Cell surface L-PHA lectin binding was measured by flow cytometry in EV- and LKB1-expressing H460 (<b>left</b>) and H2122 (<b>right</b>) KL co-mutant cells treated with azaserine (1 µM, three days). (<b>F</b>) Cell-surface L-PHA lectin binding was measured by flow cytometry in sh<span class="html-italic">GFP</span>- (control) and sh<span class="html-italic">LKB1</span>-expressing H1373 K mutant cells treated with azaserine (1 µM, three days). Mean fluorescence intensity (MFI). (<b>D</b>–<b>F</b>) Statistical significance was assessed using two-tailed Student’s <span class="html-italic">t</span>-test/each isogenic pair. n.s., not significant; * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001; **** <span class="html-italic">p</span> < 0.0001. FACS analyses were performed twice, and western blots were repeated three or more times.</p> "> Figure 2
<p>PGM3 inhibition also selectively reduces glycosylation of KL co-mutant NSCLC cells. (<b>A</b>) Schematic of the HBP. Metabolites are in black and enzymes are in red. Metabolites in the glycosylation pathway are shaded in lilac, and those in O-GlcNAcylation are shaded in light blue. (<b>B</b>) PGM3 and LKB1 expression levels were measured in EV- and LKB1-expressing H2122 (<b>left</b>) and H460 (<b>middle</b>) KL co-mutant cells and in sh<span class="html-italic">GFP</span>- and sh<span class="html-italic">LKB1</span>-expressing H1373 (<b>right</b>) K mutant cells, depleted of PGM3 using esiRNA targeting <span class="html-italic">PGM3</span>. Vinculin was used as the loading control. (<b>C</b>) Abundance of hexosamine metabolites in an isogenic pair of H460 KL co-mutant cells depleted of PGM3 by esi<span class="html-italic">PGM3</span>. Area under curve (AUC). (<b>D</b>) Wheat germ agglutinin (WGA) coupled with agarose was used to precipitate glycosylated proteins from EV- and LKB1-expressing H460 (<b>left</b>) KL co-mutant cells depleted of PGM3 by esi<span class="html-italic">PGM3</span>. Precipitated proteins were subsequently separated by SDS-PAGE then imaged. Band intensity was quantified with Photoshop, and relative band intensity was obtained by calculating a ratio between each WGA pulldown and input control. Total protein extract before the addition of WGA was used as input control. (<b>E</b>,<b>F</b>) Cell-surface SNA (<b>E</b>) and L-PHA (<b>F</b>) lectin binding was measured by flow cytometry in EV- and LKB1-expressing H2122 (<b>left</b>) and H460 (<b>middle</b>) and in sh<span class="html-italic">GFP</span>- and sh<span class="html-italic">LKB1</span>-expressing H1373 (<b>right</b>) cells depleted of PGM3 by esi<span class="html-italic">PGM3</span>. Mean fluorescence intensity (MFI). (<b>C</b>,<b>E</b>,<b>F</b>) Statistical significance was assessed using two-tailed Student’s <span class="html-italic">t</span>-test/each isogenic pair. n.s., not significant; * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001; **** <span class="html-italic">p</span> < 0.0001. FACS analyses were performed three times. Targeted metabolomics and WGA pulldown assays were performed once.</p> "> Figure 3
<p>KL co-mutant NSCLC cells require PGM3 for survival. (<b>A</b>) Schematic of the HBP. Metabolites are in black and enzymes are in red. Metabolites in the glycosylation pathway are shaded in lilac and those in O-GlcNAcylation are shaded in light blue. (<b>B</b>,<b>C</b>) Sensitivity to <span class="html-italic">PGM3</span> silencing in K mutant and KL co-mutant cells. Two isogenic pairs of KL co-mutant cells (<b>B</b>) and one isogenic pair of K mutant cells (<b>C</b>) were used. (<b>D</b>–<b>G</b>) Effect of <span class="html-italic">PGM3</span> silencing on cell death in NSCLC cells. (<b>D</b>,<b>E</b>) Representative dot plots of Annexin V/PI-stained cells with or without <span class="html-italic">PGM3</span> silencing. (<b>F</b>,<b>G</b>) Quantified data from triplicates/cell line tested in (<b>D</b>,<b>E</b>,<b>H</b>); Left<span class="html-italic">:</span> abundance of PGM3 in parental and <span class="html-italic">PGM3</span> knockout cells. Three KL co-mutant cells were used. Right<span class="html-italic">:</span> Effect of <span class="html-italic">PGM3</span> knockout on anchorage-independent growth of KL co-mutant cells. Representative images of colony formation assay (<span class="html-italic">n</span> = 3). (<b>I</b>) Quantified data from (<b>H</b>). (<b>B</b>,<b>C</b>) Statistical significance was assessed using two-tailed Student’s <span class="html-italic">t</span>-test/each isogenic pair. **** <span class="html-italic">p</span> < 0.0001. (<b>F</b>,<b>G</b>) Statistical significance was assessed using one-way ANOVA with Tukey’s multiple comparisons test. <sup>#</sup> <span class="html-italic">p</span> < 0.0001, compared to EV, with control siRNA transfection (<b>F</b>) or sh<span class="html-italic">GFP</span> with control siRNA transfection (<b>G</b>). <sup><span>$</span></sup> <span class="html-italic">p</span> < 0.0001, compared to LKB1 with control siRNA transfection (<b>F</b>) or sh<span class="html-italic">LKB1</span> with control siRNA transfection (<b>G</b>). * <span class="html-italic">p</span> < 0.0001, compared to LKB1, with <span class="html-italic">PGM3</span> siRNA transfection (<b>F</b>) or sh<span class="html-italic">LKB1</span> with <span class="html-italic">PGM3</span> siRNA transfection (<b>G</b>). (<b>I</b>) Statistical significance was assessed using two-tailed Student’s <span class="html-italic">t</span>-test/each pair of cell line. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01. Western blots, FACS analyses, and soft agar assay were all performed twice.</p> "> Figure 4
<p>PGM3 inhibitor FR054 reduces the HBP flow in both KL and K cells but selectively suppresses glyco-functionalization pathways in KL co-mutant NSCLC cells. (<b>A</b>) Schematic of the HBP, including FR054, the inhibitor of PGM3. [γ-<sup>15</sup>N]glutamine is depicted. (<b>B</b>) <b>Left</b>: time course of <sup>15</sup>N labelling in UDP-HexNAc in EV- and LKB1-expressing H460 cells cultured with [γ-<sup>15</sup>N]glutamine, treated with either DMSO (a vehicle control) or FR054 (50 µM, 3 days). <b>Right</b>: an abundance of UDP-HexNAc from labeling assay was measured by summing mass isotopologues, followed by protein normalization. (<b>C</b>) <b>Left</b>: <sup>15</sup>N labeling in UDP-HexNAc was measured in an isogenic pair of H1373 cells treated with either DMSO or FR054 (100 µM, 3 days). <b>Right</b>: <sup>15</sup>N labeling in ManNAc was measured in an isogenic pair of H1373 cells treated with either DMSO or FR054 (100 µM, 3 days). Cells were cultured with [γ-<sup>15</sup>N] glutamine for 6 h. (<b>D</b>) Effect of FR054 treatment on protein O-GlcNAcylation. One KL isogenic pair and two K isogenic pairs were used. WGA pulldown was performed (left/each cell line), and total protein extract before the addition of WGA was used as the input control (right/each cell line). Band intensity was quantified with Photoshop, and relative band intensity was obtained by calculating a ratio between each WGA pulldown band and input control. (<b>E</b>) Schematic for lectins and glycan structures. (<b>F</b>,<b>G</b>) Cell-surface LEA lectin binding was measured by flow cytometry in three isogenic pair cell lines with or without FR054 treatment for 3 days. (<b>H</b>,<b>I</b>) Cell-surface L-PHA lectin binding was measured by flow cytometry in three isogenic pair cell lines with or without FR054 treatment for 3 days. (<b>J</b>,<b>K</b>) Cell-surface SNA lectin binding was measured by flow cytometry in three isogenic pair cell lines with or without FR054 treatment for 3 days. (<b>B</b>) (left panel) Statistical significance was assessed using two-way ANOVA, followed by Tukey’s multiple comparisons test. * <span class="html-italic">p</span> < 0.05 compared to EV-FR054; <sup>#</sup> <span class="html-italic">p</span> < 0.05 compared to LKB1-DMSO; <sup><span>$</span></sup> <span class="html-italic">p</span> < 0.05 compared to LKB1-FR054. (<b>B</b>) (right panel) Statistical significance was assessed using two-tailed Student’s <span class="html-italic">t</span>-test/each isogenic pair. ** <span class="html-italic">p</span> < 0.01. (<b>C</b>,<b>F</b>–<b>K</b>) Statistical significance was assessed using two-tailed Student’s <span class="html-italic">t</span>-test/each isogenic pair. n.s., not significant; * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001; **** <span class="html-italic">p</span> < 0.0001. Targeted metabolomics and isotope tracing experiments were performed once. FACS analyses were performed twice.</p> "> Figure 5
<p>FR054 inhibits viability and clonogenicity of KL co-mutant NSCLC cells. (<b>A</b>–<b>C</b>) Sensitivity to <span class="html-italic">PGM3</span> silencing in K mutant and KL co-mutant cells. Two isogenic pairs of KL co-mutant cells (<b>A</b>), two isogenic pairs of K mutant cells (<b>B</b>), and murine NSCLC cells with either <span class="html-italic">KRAS/LKB1</span> co-mutations (KL) or <span class="html-italic">KRAS/TP53</span> co-mutations (KP) (<b>C</b>) were used. (<b>D</b>,<b>E</b>) Effect of FR054 treatment on cell death in K mutant cells and KL co-mutant cells. Three isogenic pairs were treated with either DMSO or FR054 (H460, 50 µM; H2122, 100 µM; H1373, 100 µM) for 3 days. Representative dot plots of FACS results/cell lines are shown. (<b>F</b>,<b>G</b>) Quantified FACS data from (<b>D</b>,<b>E</b>)<b>.</b> (<b>H</b>) Effect of <span class="html-italic">PGM3</span> knockout on anchorage-independent growth of K mutant cells and KL co-mutant cells (<span class="html-italic">n</span> = 3). FR054 concentration: H460, 50 µM; H2122, 100 µM; H1373, 100 µM. (<b>F</b>–<b>H</b>) Statistical significance was assessed using one-way ANOVA, followed by Tukey’s multiple comparisons test. n.s., not significant; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001; **** <span class="html-italic">p</span> < 0.0001. Cell viability assays (<span class="html-italic">n</span> = 6), FACS analysis, and soft agar assays were performed twice.</p> "> Figure 6
<p>PGM3 inhibition reduces KL co-mutant NSCLC tumor growth in vivo. (<b>A</b>) Schematic diagram of the experimental procedure. sh<span class="html-italic">GFP</span>-expressing H1373 cells (1 × 10<sup>6</sup>cells) were injected into the left flank of the mouse, and sh<span class="html-italic">LKB1</span>-expressing H1373 cells (1 × 10<sup>6</sup> cells) were injected into the right flank of the mouse. (<b>B</b>) Growth of sh<span class="html-italic">GFP</span>- and sh<span class="html-italic">LKB1</span>-expressing H1373 xenografts in the presence and absence of FR054 (500 mg/kg/dose, twice a day, 14 days total). Mean tumor volume and s.d. are shown for each group (<span class="html-italic">n</span> = 4). (<b>C</b>) Mouse weight with either vehicle control or FR054 at the day of euthanasia. (<b>D</b>) Representative Ki67 staining images of vehicle-treated and FR054-treated mice (<span class="html-italic">n</span> = 3/condition). Scale bar, 500 µm. (<b>E</b>) Ki67+ cells and total cells/tumor were quantified using Matlab. (<b>F</b>) Representative TUNEL staining of tumor tissues. 4′,6-diamidino-2-phenylindole (DAPI) was used to stain DNA. Scale bars, 100 μm. (<b>G</b>) TUNEL+ cells and total cells/tumor were quantified using Matlab. (<b>H</b>) Working model. Metabolic alterations mediated by concurrent mutations of KRAS and LKB1 created PGM3 dependence. (<b>I</b>) Kaplan-Meier plot associating <span class="html-italic">PGM3</span> mRNA expression with NSCLC (LUAD, lung adenocarcinoma (<b>left</b>) and LUSC, lung squamous carcinoma (<b>right</b>)) patient survival. Dataset is from Lung Cancer Explore, generated by UTSW (<a href="https://lce.biohpc.swmed.edu/lungcancer/" target="_blank">https://lce.biohpc.swmed.edu/lungcancer/</a>, accessed on 21 November 2021). (<b>J</b>) Kaplan-Meier plot associating <span class="html-italic">PGM3</span> mRNA expression with bladder cancer (BLCA) and breast cancer (BRCA) patient survival. Dataset is from OncoLnc (<a href="http://www.oncolnc.org/" target="_blank">http://www.oncolnc.org/</a>, accessed on 21 November 2021). (<b>B</b>) Statistical significance was assessed using a two-way ANOVA with Tukey’s multiple comparisons test. * <span class="html-italic">p</span> < 0.05 compared to DMSO. (<b>C</b>) Statistical significance was assessed using paired Student’s <span class="html-italic">t</span>-test. n.s., not significant. (<b>E</b>,<b>G</b>) Statistical significance was assessed using one-way ANOVA with Tukey’s multiple comparisons test. * <span class="html-italic">p</span> < 0.05, compared to sh<span class="html-italic">GFP</span> with vehicle treatment, <sup>#</sup> <span class="html-italic">p</span> < 0.05, compared to sh<span class="html-italic">GFP</span> with FR054 treatment, <sup><span>$</span></sup> <span class="html-italic">p</span> < 0.05, compared to sh<span class="html-italic">LKB1</span> with vehicle treatment. Tumor growth experiment was performed once.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Lines, Culture, and Reagents
2.2. Western Blot Analysis
2.3. Lectin Binding Analysis
2.4. Wheat Germ Agglutinin (WGA) Pull down Assay
2.5. Cell Proliferation and Death
2.6. RNA Interference
2.7. Soft-Agar Colony-Formation Assay
2.8. Mouse Xenografts and Tumor Tissue Analysis
2.9. 15N-Glutamine Labeling
2.10. Metabolomics
2.11. Patient Survival Data
2.12. Statistics
3. Results
3.1. GFPT2 Inhibition Selectively Reduces Glycosylation of KL Co-Mutant Cells
3.2. PGM3 Inhibition Also Selectively Reduces Glycosylation of KL Co-Mutant Cells
3.3. LKB1 Loss Confers PGM3 Dependence in KRAS-Mutant Lung Cancer Cells
3.4. PGM3 Inhibitor FR054 Reduces the HBP Flow in Both KL and K Cells but Selectively Suppresses Viability of KL co-Mutant Cells
3.5. PGM3 Inhibition Reduces KL Co-Mutant Tumor Growth In Vivo
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Lee, H.; Cai, F.; Kelekar, N.; Velupally, N.K.; Kim, J. Targeting PGM3 as a Novel Therapeutic Strategy in KRAS/LKB1 Co-Mutant Lung Cancer. Cells 2022, 11, 176. https://doi.org/10.3390/cells11010176
Lee H, Cai F, Kelekar N, Velupally NK, Kim J. Targeting PGM3 as a Novel Therapeutic Strategy in KRAS/LKB1 Co-Mutant Lung Cancer. Cells. 2022; 11(1):176. https://doi.org/10.3390/cells11010176
Chicago/Turabian StyleLee, Hyunmin, Feng Cai, Neil Kelekar, Nipun K. Velupally, and Jiyeon Kim. 2022. "Targeting PGM3 as a Novel Therapeutic Strategy in KRAS/LKB1 Co-Mutant Lung Cancer" Cells 11, no. 1: 176. https://doi.org/10.3390/cells11010176