Apolipoprotein C2 - CD36 Promotes Leukemia Growth and Presents a Targetable Axis in Acute Myeloid Leukemia

Zhang, Tian; Yang, Jiawen; Vaikari, Vijaya Pooja; Beckford, John; Wu, Sharon; Akhtari, Mojtaba; Alachkar, Houda

doi:10.1158/2643-3230.bcd-19-0077

Cited by 29 publications

(48 citation statements)

References 34 publications

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“…5 Targeting APOC2 in AML caused antileukemia activity via inhibiting CD36-ERK pathway. 3 Consistent with our findings, high APOC2 serum levels were previously found to be associated with shorter survival in pancreatic cancer. 6 Upregulation of APOC2 was also found in metastatic tumors such as breast invasive carcinoma and fast-growing lymphoma, suggesting that APOC2 may serve as a prognostic biomarker in cancer.…”

supporting

confidence: 92%

“…The data that support the findings of this study were derived from the following resources available in the pub- 1 Yiting Meng 1 Tian Zhang 2 Houda Alachkar 1,3…”

Section: A U T H O R C O N T R I B U T I O N Ssupporting

confidence: 56%

“…We recently reported APOC2 upregulation and hypomethylation in acute myeloid leukemia (AML) and more notably in AML with mixed-lineage leukemia (MLL)-rearrangements suggesting an epigenetic mech-anism regulating APOC2 expression. 3 Additionally, the transcription factor STAT1 interacts with RXRα on APOC2 promoter to drive APOC2 expression in macrophages. 4 Upregulation of APOC2 in gastrointestinal stromal tumor was associated with cancer cell proliferation, migration, and invasion.…”

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confidence: 99%

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Deregulation of apolipoprotein C2 gene in cancer: A potential metabolic vulnerability

Liu

Meng

Zhang

et al. 2021

Clinical & Translational Med

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Dear Editor, Apolipoprotein C2 (APOC2), an activator of lipoprotein lipase, participates in hydrolysis of triglycerides, very low-density lipoproteins, and high-density lipoproteins to release free fatty acids (FA). 1 FA oxidation has emerged as an important source of energy for cancer survival and growth. 2 Patterns of APOC2 genomics and transcriptomic alterations in cancer remained unexplored. Here, we characterize APOC2 deregulation in cancer by analyzing 176 studies (supplementary-methods).In 46706 samples of 34 different cancers (Table S1), amplification, mutation, and deep deletion were the main identified APOC2 alterations (Figure S1A). Approximately 1% (251 patients) had at least one genetic alteration in APOC2 with the highest frequency (9.72%) present in bladder cancer and gene amplification being the most common alteration. The highest frequency of deep deletions in APOC2 occurred in diffuse glioma (1.36%). APOC2 mutations occurred in 2.3% of non-melanoma skin cancer and at lower frequencies in other cancers (Table S2). Among the 26 different APOC2 missense and truncating mutations, two were previously reported in hypertriglyceridemia (Figure S1B; Tables S3 and S4).APOC2 was expressed at significantly higher levels in several malignancies (Figures 1 and S2), such as patient-derived glioblastoma stem cells (33.7-fold, p < 0.0001; Figure 1A), invasive ductal breast cancer (2.9fold, p < 0.0001; Figure 1B), centroblastic lymphoma (10.1fold, p < 0.0001; Figure 1C), early stage colorectal tumor (3.8-fold, p = 0.0001; Figure 1D), hypopharyngeal cancer (2.1-fold, p = 0.04; Figure 1E), clear cell renal cell carcinoma (5.9-fold, p < 0.001; Figure 1F), skin squamous cell carcinoma (2.3-fold, p = 0.023; Figure 1G), and gastric cancer (4.8-fold, p = 0.002; Figure 1H) compared with the corresponding normal tissues.

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supporting

confidence: 92%

“…The data that support the findings of this study were derived from the following resources available in the pub- 1 Yiting Meng 1 Tian Zhang 2 Houda Alachkar 1,3…”

Section: A U T H O R C O N T R I B U T I O N Ssupporting

confidence: 56%

mentioning

confidence: 99%

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Deregulation of apolipoprotein C2 gene in cancer: A potential metabolic vulnerability

Liu

Meng

Zhang

et al. 2021

Clinical & Translational Med

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“… 8 The human APOC2 gene is located in the APOE‐APOC1‐APOC4‐APOC2 gene cluster and its transcriptional control is very complicated. 9 , 10 APOC2 is synthesized primarily by liver to bind lipids and lipoprotein lipase (LPL); 11 however, it is also expressed in other tissues, including intestine, where it regulates local lipolysis. 12 , 13 , 14 As a key regulator of the TRL metabolism, APOC2 can guide lipoproteins to active LPL sites and act as a physiological activator of LPL, which is the main enzyme of plasma triglycerides (TG) hydrolysis.…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein C‐II induces EMT to promote gastric cancer peritoneal metastasis via PI3K/AKT/mTOR pathway

Wang

Yang

et al. 2021

Clinical & Translational Med

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Background Peritoneal metastasis (PM) occurs frequently in patients with gastric cancer (GC) and confers poor survival. Lipid metabolism acts as a non‐negligible regulator in epithelial–mesenchymal transition (EMT), which is crucial for the metastasis of GC. As apolipoprotein C2 (APOC2) is a key activator of lipoprotein lipase for triglyceride metabolism, the exact mechanism of APOC2 remains largely unknown in GC. Methods Tandem mass tags identified differentially expressed proteins between human PM and GC tissues, and showed that APOC2 overexpressed in PM tissues, which was further confirmed by immunoblotting, immunohistochemistry, and ELISA. Global gene expression changes were identified in APOC2 knockdown cells via RNA‐sequencing. The role of APOC2 in lipid metabolism of GC cells was assessed via the Seahorse XF analyzer and lipid staining assays. The biological role of APOC2 in GC cells was determined by 3D Spheroid invasion, apoptosis, colony formation, wound healing, transwell assay, and mouse models. The interaction between APOC2 and CD36 was analyzed by co‐immunoprecipitation and biolayer interferometry. The underlying mechanisms were investigated using western blot technique. Results APOC2 overexpressed in GC PM tissues. Upregulation of APOC2 correlated with a poor prognosis in GC patients. APOC2 promoted GC cell invasion, migration, and proliferation via CD36‐mediated PI3K/AKT/mTOR signaling activation. Furthermore, APOC2‐CD36 axis upregulated EMT markers of GC cells via increasing the phosphorylation of PI3K, AKT, and mTOR. Knockdown either APOC2 or CD36 inhibited the malignant phenotype of cancer cells, and delayed GC PM progression in murine GC models. Conclusion APOC2 cooperates with CD36 to induce EMT to promote GC PM via PI3K/AKT/mTOR pathway. APOC2‐CD36 axis may be a potential target for the treatment of aggressive GC.

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“…APOC2 is synthesized mainly by the liver and is then secreted into the plasma to bind lipids and lipoprotein lipase (LPL); however, it is also expressed in other tissues, including macrophages and the intestine, where it regulates lipolysis at the local level (12)(13)(14). APOC2 plays an important role in TRL metabolism because it can guide lipoproteins to active LPL sites and act as a physiological activator of LPL, which is the main enzyme that hydrolyzes plasma triglycerides (TG) on TRLs (15)(16)(17). Therefore, APOC2 can provide energy transport and storage for cells by regulating lipid metabolism (18).…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein C-II induces EMT to Promote Gastric Cancer Peritoneal Metastasis via PI3K/AKT/mTOR Pathway

Wang

Yang

et al. 2021

Preprint

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Background: Peritoneal metastasis (PM) occurs frequently in patients with gastric cancer (GC) and confers poor survival. Lipid metabolism and epithelial-mesenchymal transition (EMT) play an important role in GC metastasis. As Apolipoprotein C-II (APOC2) is a key protein in lipid metabolism, few studies have investigated the role of APOC2 in PM. This study aims to elucidate the potential molecular mechanism of APOC2 in the PM of GC.Methods: The Tandem Mass Tagging (TMT) method followed by liquid chromatography-tandem mass spectrometry-based proteomics analysis was used to compare the levels of differentially expressed proteins between human PM and GC tissues. APOC2 expression was evaluated by immunoblotting, and immunohistochemistry analysis (n = 111). APOC2 over-expression and knock-down expression cell models were developed and tested in vitro. RNA sequencing analysis evaluated the changes in gene expression after APOC2 knockdown in GC cells. The Agilent Seahorse XF platform and lipid staining assay were used to evaluate the role of APOC2 in lipid metabolism of GC cells. Spheroid cell invasion assay, apoptosis assay, colony formation assay, wound-healing assays, and transwell assays were performed and peritoneal implants into nude mice were done to assess the biological effects of APOC2. The underlying mechanisms were investigated using Western blot, inhibitor or activator treatment assays.Results: APOC2 was highly abundant in GC cells and PM tissues. And high APOC2 levels in GC tissues correlated with poor patient prognosis. Knockdown of APOC2 inhibited the malignant phenotype of cancer cells and EMT significantly. Massive gene expression alterations after APOC2 knockdown, which were associated with various signaling pathways, especially the PI3K/AKT signaling pathway and lipid metabolism. Furthermore, the regulatory effects of APOC2 on the EMT were partially attributed to the PI3K/AKT/mTOR signaling pathway. The results in vivo also showed that APOC2 modulated GC PM.Conclusions: We verified that knockdown of APOC2 suppressed GC cell Lipid metabolism, proliferation, migration, invasion, and EMT, accompanied by inactivation of PI3K/AKT/mTOR signaling pathway. APOC2 overexpression had the opposite effects GC cell phenotypes and mechanisms. Collectively, our results identified APOC2 in PM as a potential therapeutic target.

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Apolipoprotein C2 - CD36 Promotes Leukemia Growth and Presents a Targetable Axis in Acute Myeloid Leukemia

Cited by 29 publications

References 34 publications

Deregulation of apolipoprotein C2 gene in cancer: A potential metabolic vulnerability

Deregulation of apolipoprotein C2 gene in cancer: A potential metabolic vulnerability

Apolipoprotein C‐II induces EMT to promote gastric cancer peritoneal metastasis via PI3K/AKT/mTOR pathway

Apolipoprotein C-II induces EMT to Promote Gastric Cancer Peritoneal Metastasis via PI3K/AKT/mTOR Pathway

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