High expression of ALDH1A3 might independently influence poor progression‐free and overall survival in patients with glioma via maintaining glucose uptake and lactate production

Ni, Wei; Xia, Yaoxiong; Lin, Li‐Rong; Fan, Wen; Hu, Dong; Bi, Yuxu; Qi, Junhui

doi:10.1002/cbin.11257

Cited by 11 publications

(10 citation statements)

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“…Previous studies suggest that ALDH1A3 is closely associated with the colony formation, sphere formation, tumorigenesis, and angiogenic activity of cancer cells (15). High expression of ALDH1A3 predicts poor prognosis in glioma (18), melanoma (19), glioblastoma (20), and breast cancer (21). However, the role of ALDH1A3 has not so far been reported under physiological circumstances in PDAC cells.…”

Section: Discussionmentioning

confidence: 98%

ALDH1A3 Accelerates Pancreatic Cancer Metastasis by Promoting Glucose Metabolism

et al. 2020

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Background: The aldehyde dehydrogenase 1 family member A3 (ALDH1A3) is a key enzyme associated with a variety of metabolic processes, including glucose metabolism. We recently uncovered that glucose metabolism played an essential role in promoting metastasis of pancreatic ductal adenocarcinoma (PDAC). As ALDH1A3 labels an aggressive subtype of PDAC, we hypothesized that ALDH1A3 functionally promoted PDAC metastasis via its metabolic effect on glucose metabolism.Methods: Expression of ALDH1A3 was detected in human PDAC tissues by immunohistochemistry. ALDH1A3 was knocked down or overexpressed in PDAC cells by either shRNA or overexpression vector. The functional roles of ALDH1A3 were characterized in vitro and in vivo. Transcriptional profiling via RNA-sequencing was used to explore the possible underlying molecular mechanisms. Glucose uptake, extracellular lactate, and ATP production were measured to access the metabolic influence of ALDH1A3 on PDAC cells.Results: ALDH1A3 was associated with poor prognosis in PDAC patients. Functionally, ALDH1A3 promoted PDAC metastasis in vitro and in vivo. Further studies revealed that ALDH1A3 activated PI3K/AKT/mTOR signaling pathway and its downstream target-PPARγ (peroxisome proliferator-activated receptor gamma). This led to increase the expression of HK2 (hexokinase 2), which subsequently enhanced the glycolysis in PDAC cells. Additionally, the pharmacological inhibition of PPARγ activity in ALDH1A3-positive cells impaired glycolytic genes expression, PI3K/AKT/mTOR activity and cellular glycolysis.Conclusions: ALDH1A3 promotes PDAC metastasis via its metabolic influence on glucose metabolism. PPARγ and its downstream PI3K/AKT/mTOR signaling pathway maybe involved in this process.

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Section: Discussionmentioning

confidence: 98%

ALDH1A3 Accelerates Pancreatic Cancer Metastasis by Promoting Glucose Metabolism

et al. 2020

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“…studies on the correlation between PKM2 and its role in glioma (11,32,33), we studied the relationship between PKM2 and glioma. Although previous studies have shown the effects of PKM2 inhibition of glioma cells (13,17,18,34), we attempted to identify the mechanism of PKM2 inhibition. We also anticipated that our novel findings about the role of PKM2 in glioma might facilitate the application of PKM2-targeting in glioma in clinical applications.…”

Section: Discussionmentioning

confidence: 99%

“…Pyruvate kinase M2 (PKM2) is a key rate-limiting enzyme of glycolysis in cancer cells. It has been demonstrated to contribute to the genesis and proliferation of glioma cells (13), and has thus recently gained much attention.…”

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confidence: 99%

PKM2 Is Overexpressed in Glioma Tissues, and Its Inhibition Highly Increases Late Apoptosis in U87MG Cells With Low-density Specificity

PARK

LEE

et al. 2022

In Vivo

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Background/Aim: Pyruvate kinase M2 (PKM2) functions as an important rate-limiting enzyme in aerobic glycolysis and is involved in tumor initiation and progression. However, there are few studies on the correlation between PKM2 expression and its role in glioma. Materials and Methods: PKM2 expression was immunohistochemically examined in human brain tumor samples. Furthermore, we studied the effects of two PKM2 inhibitors (shikonin and compound 3K) on the U87MG glioma cell line. Results: PKM2 was overexpressed in most glioma tissues when compared to controls. Interestingly, glioma-adjacent tissues from showed slight PKM2 overexpression. This suggests that PKM2 overexpression maybe an important trigger factor for glioma tumorigenesis. We found that the PKM2 inhibitor shikonin was effective against U87MG cells at a relatively low dose and was largely dependent on low cellular density compared to the effects of the anticancer drug vincristine. Shikonin highly increased late-apoptosis of U87MG cells. We also demonstrated that autophagy was involved in the increase in late-apoptosis levels caused by shikonin. Although vincristine treatment led to a high level of G 2 -phase arrest in U87MG cells, shikonin did not increase G 2 arrest. Cotreatment with two PKM2 inhibitors, shikonin and compound 3K, increased the inhibitory effects. Conclusion: Combination therapy with PKM2 inhibitors together might be more effective than combination therapy with anticancer drugs.Our findings encourage the application of PKM2-targeting in gliomas, and lay the foundation for the development of PKM2 inhibitors as promising antitumor agents for glioma.

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“…An increasing body of evidence suggests that ALDHs target inhibitors could inhibit stem-like cell proliferation of gliomas (18,34,35). Furthermore, ALDH1A3 could reportedly affect glioma glucose metabolism and is recognized as a stem-like cells biomarker (36,37). Besides, ALDH1A1 and ALDH1A2 have been documented as glioma migration-associated genes (38)(39)(40), while ALDH1A1 also participated in GBM resistance to temozolomide (17,19).…”

Section: Discussionmentioning

confidence: 99%

The ALDH Family Contributes to Immunocyte Infiltration, Proliferation and Epithelial-Mesenchymal Transformation in Glioma

Wang

Tan

et al. 2022

Front. Immunol.

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Gliomas are malignant tumors that originate from the central nervous system. The aldehyde dehydrogenase family has been documented to affect cancer progression; however, its role in gliomas remains largely unexplored. Bulk RNA-seq analysis and single-cell RNA-Seq analysis were performed to explore the role of the aldehyde dehydrogenases family in gliomas. Training cohort contained The Cancer Genome Atlas data, while data from Chinese Glioma Genome Atlas and Gene Expression Omnibus were set as validation cohorts. Our scoring system based on the aldehyde dehydrogenases family suggested that high-scoring samples were associated with worse survival outcomes. The enrichment score of pathways were calculated by AUCell to substantiate the biofunction prediction results that the aldehyde dehydrogenases family affected glioma progression by modulating tumor cell proliferation, migration, and immune landscape. Tumor immune landscape was mapped from high-scoring samples. Moreover, ALDH3B1 and ALDH16A1, two main contributors of the scoring system, could affect glioblastoma cell proliferation and migration by inducing cell-cycle arrest and the epithelial-mesenchymal transition. Taken together, the aldehyde dehydrogenases family could play a significant role in the tumor immune landscape and could be used to predict patient prognosis. ALDH3B1 and ALDH16A1 could influence tumor cell proliferation and migration.

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High expression of ALDH1A3 might independently influence poor progression‐free and overall survival in patients with glioma via maintaining glucose uptake and lactate production

Cited by 11 publications

References 50 publications

ALDH1A3 Accelerates Pancreatic Cancer Metastasis by Promoting Glucose Metabolism

ALDH1A3 Accelerates Pancreatic Cancer Metastasis by Promoting Glucose Metabolism

PKM2 Is Overexpressed in Glioma Tissues, and Its Inhibition Highly Increases Late Apoptosis in U87MG Cells With Low-density Specificity

The ALDH Family Contributes to Immunocyte Infiltration, Proliferation and Epithelial-Mesenchymal Transformation in Glioma

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