Identification of ATP citrate lyase as a positive regulator of glycolytic function in glioblastomas

Beckner, Marie E.; Fellows-Mayle, Wendy; Zhang, Zhe; Agostino, Naomi R.; Kant, Jeffrey A.; Day, Billy W.; Pollack, Ian F.

doi:10.1002/ijc.24918

Cited by 104 publications

(79 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Beckner et al [10] reported that glycolytic enzymes are abundant in pseudopodia formed by U87 astrocytoma cells, and that glycolysis alone can support glioma cell migration. Recently, robust migration of glioblastoma cells has been previously demonstrated under glycolytic conditions and their pseudopodia contain increased glycolytic and decreased mitochondrial enzymes [11].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Network in Glioma’s Invadopodia Displays an Activated State Both in Situ and in Vitro: Potential Functional Implications

Arismendi-Morillo

Hoa²,

Ge³

et al. 2012

Ultrastructural Pathology

View full text Add to dashboard Cite

Gliomas are typically characterized by their infiltrative nature, and the prognosis can be linked to the invasive nature of the tumoral cells. Glioblastoma multiforme are very invasive cancers and this contributes to their lethality. The invadopodia are considered essential for their motility. Human glioma cell invadopodia were examined with transmission electron and immunofluorescent microscopy. By electron microscopy, in situ gliomas (fibrillary astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, pilocytic astrocytoma) show mitochondria with a dense matrix condensed configuration, indicating an active state. The mitochondria were frequently in close contact with an extended smooth endoplasmic reticulum displaying an endoplasmic reticulum subfraction associated with mitochondria. Mitochondria were seen within the filopodia that were penetrating into the extracellular matrix. The activated mitochondria and smooth endoplasmic reticulum were also detected within the invadopdia, which was associated microblood vessels. Fluorescent microscopy confirmed that D54 and U251 glioma cells growing in vitro also contained filopodia with mitochondria. The U251 glioma cells' filopodia that penetrated through 1.2-μm pores of transwell chambers also contained mitocondria, suggesting that the mitochondria are actively involved in the invasion process. Migration and invasion of tumor cells requires an increase in cellular motility and involves formation of lamellipodia, protrusions of the plasma membrane, and individual filopodia [ 1 ]. Gliomas are typically characterized by their infiltrative nature, resulting in a poorly demarcated interface between tumor and normal brain tissue. Their poor prognosis can be linked to the invasive nature of these cells. The motility of these tumor cells is correlated with the presence of invadopodia [ 2 ], and, consequently, more insight is necessary into their structural and molecular aspects. Evidence of robust invadopodia activity in glioblastoma multiforme cells has been reported [ 3 , 4 ]. Because of the significant impact of invadopodia in oncological events such as cell invasion and matrix degradation, more insight into structural and molecular aspects is needed [ 2 ]. The dynamic assembly of invadopodia is still not well understood [ 2 ], and little is known of the alterations in mitochondrial structure and function that contribute to cell mobility [ 5 ]. This paper describes two prominent structural features of the mitochondrial network present within the glioma´s invadopodia that we have recently observed. We believe these two features (activated mitochondria and smooth ER, along with mitochondria contained within the filopodia) might provide researchers with possible targets for future therapies that can control glioma invasiveness.

show abstract

Section: Discussionmentioning

confidence: 99%

Mitochondrial Network in Glioma’s Invadopodia Displays an Activated State Both in Situ and in Vitro: Potential Functional Implications

Arismendi-Morillo

Hoa²,

Ge³

et al. 2012

Ultrastructural Pathology

View full text Add to dashboard Cite

show abstract

“…Upregulation of ACLy has been found in several types of cancer (31–36). The mechanism by which ACLy is involved in the survival machinery of cancer cells might be complex.…”

Section: Discussionmentioning

confidence: 99%

ATP Citrate Lyase Mediates Resistance of Colorectal Cancer Cells to SN38

Zhou

Bollu

Tozzi

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Combination chemotherapy is standard for metastatic colorectal cancer (CRC); however, nearly all patients develop drug resistance. Understanding the mechanisms that lead to resistance to individual chemotherapeutic agents may enable identification of novel targets and more effective therapy. Irinotecan is commonly used in first- and second-line therapy for patients with metastatic CRC, with the active metabolite being SN38. Emerging evidence suggests that altered metabolism in cancer cells is fundamentally involved in the development of drug resistance. Using Oncomine and unbiased proteomic profiling, we found that ATP citrate lyase (ACLy), the first-step rate-limiting enzyme for de novo lipogenesis, was upregulated in CRC compared to its levels in normal mucosa and in chemoresistant CRC cells compared to isogenic chemo-naïve CRC cells. Overexpression of exogenous ACLy by lentivirus transduction in chemo-naïve CRC cells led to significant chemoresistance to SN38 but not to 5-fluorouracil or oxaliplatin. Knockdown of ACLy by siRNA or inhibition of its activity by a small-molecule inhibitor sensitized chemo-naïve CRC cells to SN38. Furthermore, ACLy was significantly increased in cancer cells that had acquired resistance to SN38. In contrast to chemo-naïve cells, targeting ACLy alone was not effective in re-sensitizing resistant cells to SN38, due to a compensatory activation of the AKT pathway triggered by ACLy suppression. Combined inhibition of AKT signaling and ACLy successfully re-sensitized SN38-resistant cells to SN38. We conclude that targeting ACLy may improve the therapeutic effects of irinotecan and that simultaneous targeting of ACLy and AKT may be warranted to overcome SN38 resistance.

show abstract

“…In addition to its role in fatty acid synthesis, ACLY reinforces the Warburg effect by preventing the accumulation of cytosolic citrate, which is a glycolysis inhibitor. 75,90,91 Glucose provides 60% of the carbon used for fatty acid synthesis. 22 The continued export of citrate from the Krebs cycle may cause a carbon deficit, which can be replenished by the anaplerotic flux derived from the metabolism of glutamine to continue fatty acid synthesis and cellular proliferation (Fig.…”

Section: Tumor Cells Synthesize Fatty Acids and Nucleotides At High Rmentioning

confidence: 99%

Tumor cell metabolism

Romero-García

López‐González

Báez-Viveros

et al. 2011

Cancer Biology & Therapy

186

118

View full text Add to dashboard Cite

Identification of ATP citrate lyase as a positive regulator of glycolytic function in glioblastomas

Cited by 104 publications

References 65 publications

Mitochondrial Network in Glioma’s Invadopodia Displays an Activated State Both in Situ and in Vitro: Potential Functional Implications

Mitochondrial Network in Glioma’s Invadopodia Displays an Activated State Both in Situ and in Vitro: Potential Functional Implications

ATP Citrate Lyase Mediates Resistance of Colorectal Cancer Cells to SN38

Tumor cell metabolism

Contact Info

Product

Resources

About