ING5 inhibits aerobic glycolysis of lung cancer cells by promoting TIE1-mediated phosphorylation of pyruvate dehydrogenase kinase 1 at Y163
Haihua Zhang1, Xinli Liu2, Junqiang Li3, Jin Meng4, Wan Huang5, Xuan Su1, Xutao Zhang6, Guizhou Gao1, Xiaodong Wang1, Haichuan Su3(), Feng Zhang2(), Tao Zhang1()
. Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, China . Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an 710038, China . Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, China . Department of Pharmacy, the Medical Security Centre, Chinese PLA General Hospital, Beijing 100091, China . National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi’an 710038, China . Aerospace Clinical Medical Center, School of Aerospace Medicine, Fourth Military Medical University, Xi’an 710038, China
Aerobic glycolysis is critical for tumor growth and metastasis. Previously, we have found that the overexpression of the inhibitor of growth 5 (ING5) inhibits lung cancer aggressiveness and epithelial–mesenchymal transition (EMT). However, whether ING5 regulates lung cancer metabolism reprogramming remains unknown. Here, by quantitative proteomics, we showed that ING5 differentially regulates protein phosphorylation and identified a new site (Y163) of the key glycolytic enzyme PDK1 whose phosphorylation was upregulated 13.847-fold. By clinical study, decreased p-PDK1Y163 was observed in lung cancer tissues and correlated with poor survival. p-PDK1Y163 represents the negative regulatory mechanism of PDK1 by causing PDHA1 dephosphorylation and activation, leading to switching from glycolysis to oxidative phosphorylation, with increasing oxygen consumption and decreasing lactate production. These effects could be impaired by PDK1Y163F mutation, which also impaired the inhibitory effects of ING5 on cancer cell EMT and invasiveness. Mouse xenograft models confirmed the indispensable role of p-PDK1Y163 in ING5-inhibited tumor growth and metastasis. By siRNA screening, ING5-upregulated TIE1 was identified as the upstream tyrosine protein kinase targeting PDK1Y163. TIE1 knockdown induced the dephosphorylation of PDK1Y163 and increased the migration and invasion of lung cancer cells. Collectively, ING5 overexpression—upregulated TIE1 phosphorylates PDK1Y163, which is critical for the inhibition of aerobic glycolysis and invasiveness of lung cancer cells.
Just Accepted Date: 26 July 2024Online First Date: 14 September 2024Issue Date: 29 October 2024
Cite this article:
Haihua Zhang,Xinli Liu,Junqiang Li, et al. ING5 inhibits aerobic glycolysis of lung cancer cells by promoting TIE1-mediated phosphorylation of pyruvate dehydrogenase kinase 1 at Y163[J]. Front. Med.,
2024, 18(5): 878-895.
Fig.1 Quantitative analysis of phospho-proteome upon ING5 overexpression. (A) Quantitative ratio (L/H) distribution of phosphorylated protein influenced by ING5 overexpression. The figure shows the protein ratio (log (protein ratio), with base = 2) of each differentially expressed protein. Proteins with upregulated phosphorylation are located right of zero of the x-axis, whereas proteins with downregulated phosphorylation are located left of zero of the x-axis. (B) Enrichment and clustering analysis of biological processes based on Gene Ontology annotation. (C) Enrichment and clustering analysis of molecular function based on Gene Ontology annotation. (D) Enrichment and clustering analysis of cellular components based on Gene Ontology annotation. (E) Enrichment and clustering analysis of KEGG pathways. (F) Enrichment and clustering analysis of protein domain. (G) ING5 participated in the modified protein interaction network of the pathway map05230 central carbon metabolism in cancer. The circle represents the protein; the size of the circle represents the number of interacting proteins, and the different colors represent the Q1–Q4 proteins. (H) Difference ratio information of all phosphorylation sites. The horizontal coordinate is the ratio value rank, and the vertical coordinate is the log2 ratio value. The Q1, Q2, Q3, and Q4 sites are distinguished by color, and the PDK1-Y163 site is separately marked.
Fig.2 Y163 is a new phosphorylation site in PDK1 upregulated by ING5 overexpression, which positively correlated with better prognosis in patients with lung cancer. (A) LC–MS/MS spectrum of peptide HNDVIPTMAQGVIEYK of PDK1. (B) Phosphorylation of PDK1 Y163 is upregulated in ING5-overexpressing lung cancer cells by Western blot. Phosphorylation of PDK1 Y376 shows no significant change between the control and high-ING5-expression group. Actin was used as an internal loading control. (C) Phosphorylation of PDK1 Y163 is downregulated in ING5-knockdown lung cancer cells. Phosphorylation of PDK1 Y376 shows no significant change between the control and ING5 knockdown groups. (D, E) Representative images of NSCLC and adjacent noncancerous tissues with p-PDK1 Y163 staining. Scale bar, 200 μmol/L and 50 μmol/L. (F) The expression of p-PDK1 Y163 in NSCLC was lower than that in adjacent noncancerous specific antibody (P < 0.001). (G) Kaplan–Meier overall survival (OS) analysis based on NSCLC patients with high and low p-PDK1 Y163 levels (HR = 0.596, 95% CI = 0.396–0.979, P = 0.041, log-rank test).
Clinicopathological variables
Total (n)
p-PDK1 (Y163) expression (IHC)
Low
High
χ2
P value
Age
< 60
45
20
25
0.085
0.771
≥ 60
53
22
31
Gender
Male
55
21
34
1.107
0.293
Female
43
21
22
Tumor location
Left lung
43
18
25
0.005
0.943
Right lung
54
23
31
Tumor invasion
T1
20
10
10
9.033
0.029*
T2
51
17
34
T3
22
10
12
T4
5
5
0
Lymph node metastases
N0
44
16
28
1.139
0.286
N1–N3
53
25
28
Metastasis
No
97
55
42
0.750
0.387
Yes
1
1
0
Clinical stage
I–II
52
19
33
2.398
0.122
III–IV
45
24
22
Pathological grade
Well and moderate
84
38
46
1.347
0.246
Poorly and not
14
4
10
Tab.1 Correlation of p-PDK1 Y163 expression with clinicopathological features of NSCLC
Fig.3 Y163 phosphorylation negatively regulates PDK1 kinase activity, and it is necessary for the ING5-reversed Warburg effect. (A) LC–MS/MS spectrum of peptide YHGHSMSDPGVSTR of PDHA1. Phosphorylation of PDHA1 S293 is downregulated by ING5 overexpression by quantitative phospho-proteomics. (B) ING5 overexpression decreased the phosphorylation of PDHA1 S293 by Western blot. Actin was used as an internal loading control. (C) ING5 overexpression (ING5) increased the enzyme activity of PDH. (D) ING5 overexpression enhanced cancer cell oxygen consumption. (E) ING5 overexpression downregulated HIF-1α and LDHA by Western blot. Actin was used as an internal loading control. (F) ING5 overexpression inhibited LDH activity. (G) ING5 overexpression decreased cancer cell lactic acid (LD) production. (H) Phosphorylation of PDK1 Y163 was decreased by Y163F mutation. ING5 overexpression—decreased PDHA1 S293 phosphorylation was impaired by PDK1 Y163F mutation. Actin was used as an internal loading control. (I) ING5 overexpression—increased PDH enzyme activity was abolished by PDK1 Y163F mutation. (J) ING5 overexpression—enhanced oxygen consumption was decreased by PDK1 Y163F mutation. (K) PDK1 Y163F phospho-dead mutation impaired the downregulating effects of ING5 overexpression on HIF-1α and LDHA levels. (L) ING5 overexpression—downregulated LDH activity was impaired by PDK1 Y163F mutation. (M) ING5 overexpression–decreased lactic acid production was impaired by PDK1 Y163F mutation. Data of (C, D, F, G, I, J, L, and M) are shown as the mean plus standard error of three independent experiments (n = 3 samples). Statistical analysis was performed by one-way ANOVA. *P < 0.05 and **P < 0.01 versus the NC group.
Fig.4 PDK1 Y163 phosphorylation is required for ING5-inhibited invasiveness of lung cancer cells in vitro and in vivo. Cells were divided into the following groups: (1) control A549 cells (control); (2) ING5-overexpressing cells (ING5); (3) ING5-overexpressing A549 cells with PDK1 knockdown (ING5-PDK1 KD); (4) ING5-PDK1 KD cells rescued with wild-type PDK1 (ING5-PDK1 WT); (5) ING5-PDK1 KD cells rescued with phospho-dead Y163F mutant PDK1 (ING5-PDK1 Y163F). (A) PDK1 Y163F mutation significantly increased the proliferation of lung cancer A549 cells with ING5 overexpression. (B) PDK1 Y163F mutation significantly increased colony formation of lung cancer A549 cells with ING5 overexpression. Representative pictures are shown. Colony numbers were quantified. (C) Wound-healing assay was performed to show the promoting effects of PDK1 Y163 mutation on the migration of A549 ING5-overexpressing cells. A scratch wound was made on the cell surface, and cells were photographed at 0 h, 8 h, 16 h, 20 h, and 24 h. Representative pictures are shown. (D) PDK1 Y163 mutation accelerated the Transwell migration of A549 ING5-overexpressing cells. The migrated cells were photographed (100× magnification). Representative pictures are shown. (E) PDK1 Y163 mutation promoted the Transwell invasive abilities of A549 ING5-overexpressing cells. The invaded cells were photographed (100× magnification). Representative pictures are shown. (F) Effects of PDK1 Y163 mutation on the expression of EMT markers in A549 ING5-overexpressing cells. Actin was used as an internal loading control. (G) Mice were injected subcutaneously with 5 × 106 lung cancer A549 cells. At the end of the experiment, mice were sacrificed and photographed. (H) Tumor growth curves revealed that the tumor volumes were significantly higher in mice with ING5-PDK1 Y163F cells. (I) Survival analysis showed that mice with ING5 OE cells had better overall survival than those with control cells (P = 0.0007), whereas mice with ING5-PDK1 Y163F cells had worse overall survival than those with ING5-PDK1 WT cells (P = 0.0023). (J) Mice were injected through the tail vein with 5 × 106 lung cancer A549 cells. On day 45 after tumor cell injection, mice were sacrificed, and the lungs were photographed. Gross images of the lungs showed lung-metastasized tumors in different groups. (K) Representative images of HE staining for lung tissues were provided (scale bar, 200 μm). (L) Tumor index of mice from different groups. (M) Lung weight of mice from different groups. Statistical analysis was performed using two-way ANOVA, followed by post-hoc tests. *P < 0.05 and **P < 0.01 versus the NC group.
Fig.5 TIE1 was identified as an anti-tumor TPK upregulated by ING5. (A) Results of the top 10 targeted genes were shown from a TPK siRNA library-based screening of invasion assay. (B) TIE1 mRNA expression in diverse tumor and normal tissues using the GEPIA2 database. Red, tumor samples; green, normal control sample. TIE1 expression was decreased in 11 tumors: LUAD (lung adenocarcinoma), BLCA (bladder urothelial carcinoma), BRCA (breast invasive carcinoma), CESC (cervical squamous cell carcinoma and endocervical adenocarcinoma), COAD (colon adenocarcinoma), KICH (kidney chromophobe), KIRP (kidney renal papillary cell carcinoma), LUSC (lung squamous cell carcinoma), THCA (thyroid carcinoma), UCEC (uterine corpus endometrial carcinoma), and UCS (uterine carcinosarcoma). (C) The mRNA expression level of TIE1 was analyzed in LUAD and normal tissues using TCGA samples. *P < 0.05, compared with normal tissues. (D) TIE1 protein expression levels in LUAD and normal tissue were analyzed using CPTAC samples. (E) Kaplan–Meier overall survival curves showed that the high expression level of TIE1 predicts longer survival. (F) Spearman correlation analysis showed that the expression of TIE1 was positively correlated with ING5 expression. (G, H) Representative images and results of Transwell migration assays of the TIE1-knockdown (sh-TIE1-1 and sh-TIE1-2) A549 control group and A549-ING5-OE control group. (I, J) Representative images and results of Transwell invasion assays of the TIE1-knockdown (sh-TIE1-1 and sh-TIE1-2) A549 control group and A549-ING5-OE control group. Data of (G−J) are shown as the mean plus standard error of three independent experiments (n = 3 samples).
Fig.6 TIE1 directly phosphorylates PDK1 at Y163, which is promoted by ING5. (A) PDK1 Y163 is specifically phosphorylated by rTIE1 by in vitro kinase assay. An antibody that specifically recognizes p-PDK1 Y163 was used. (B) Immunofluorescence assay showed the mitochondrial location of TIE1 in lung cancer cells. Representative images are presented (600×). (C) Mitochondrial localization of TIE1 in A549 cells was confirmed by transmission electron microscopy (TEM). Scale bars: 5.0 μm (left), 1.0 μm (middle), and 500 nm (right). (D, E) ING5 overexpression-promoted PDK1Y163 phosphorylation was impaired by TIE1 knockdown by Western blot. (F, G) Expression of TIE1 and p-PDK1Y163 in ING5-overexpressing or knockdown lung cancer cells by Western blot. (H) A graphic illustration of the proposed mechanism in this study. In brief, ING5 overexpression upregulates TIE1, which phosphorylates PDK1 at Y163, leading to the dephosphorylation-dependent activation of PDHA1 and subsequent increased oxidative phosphorylation. In addition, ING5 overexpression downregulates HIF-1α/LDHA1, thereby decreasing glycolysis.
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