- Letter to the Editor
- Open Access
Modulation of lipolysis and glycolysis pathways in cancer stem cells changed multipotentiality and differentiation capacity toward endothelial lineage
- Ayda Pouyafar1,
- Milad Zadi Heydarabad1,
- Jalal Abdolali Zade2,
- Reza Rahbarghazi†2, 3Email authorView ORCID ID profile and
- Mehdi Talebi†2Email author
© The Author(s) 2019
- Received: 8 February 2019
- Accepted: 21 March 2019
- Published: 27 March 2019
Cancer stem cells obtain energy demand through the activation of glycolysis and lipolysis. It seems that the use of approached targeting glycolysis and lipolysis could be an effective strategy for the inhibition of cancer stem cells. In the current experiment, we studied the potential effect of glycolysis and lipolysis inhibition on cancer stem cells differentiation and mesenchymal–epithelial-transition capacity. Cancer stem cells were enriched from human ovarian cells namely SKOV3 by using MACS technique. Cells were exposed to Lonidamine, an inhibitor of glycolysis, and TOFA, a potent inhibitor of lipolysis for 7 days in endothelial differentiation medium; EGM-2 and cell viability was studied by MTT assay. At the respective time point, the transcription level of genes participating in EMT such as Zeb-1, -2, Vimentin, Snail-1, -2 and VE-cadherin were measured by real-time PCR analysis. Our data noted that the inhibition of lipolysis and glycolysis could decrease cell viability compared to the control of cancer stem cells. The inhibition of glycolysis prohibited the expression of Zeb-1, Snails, and Vimentin while increased endothelial differentiation rate indicated by the expression of VE-cadherin. In contrast, the inhibition of lipolysis increased EMT associated genes and reduced endothelial differentiation rate by suppressing the transcription of VE-cadherin. Notably, the simultaneous inhibition of glycolysis and lipolysis had moderate effects on the transcription of EMT genes. We concluded that the modulation of the metabolic pathway of glycolysis in ovarian CSCs is more effective than the inhibition of lipolysis in the control of angiogenesis potential and stemness feature.
- Ovarian cancer stem cells
First, we appreciate you for the invitation to provide a response to the Letter-to-the-Editor. Over the past decades, a small fraction of cell populations named cancer stem cells (CSCs) is identified inside the cancer niche, contributing to rapid cancer expansion and resistance to chemotherapeutic agents. In fact, CSCs possess self-renewal, clonogenic and trans-differentiation capacities . Based on the great body of science, CSCs are responsible for the origin, growth, recurrence and cancers metastasis . Thus, any modalities targeting the dynamic growth of CSCs could yield a better therapeutic outcome.
It is found that CSCs change their phenotype via engaging epithelial–mesenchymal transition (EMT) mechanism. These mechanisms adopt CSCs to environmental stimuli and help to escape from the immune-related responses . It is well-established that multiple factors, including ZEB 1, 2, Snail 1, 2, Twist 1, 2, actively participate in the EMT process. The induction of these factors correlates with EMT, contributing to tumor’s invasive behavior and induction of metastasis. Cancer cells, especially CSCs require on-demand energy for dynamics growth, differentiation during the development of tumor mass . Depending on the entity of tumor, cancer cells supply energy requirement by biochemical reactions related to glycolysis, lipolysis, and proteolysis. Similar to the normal cells, cancer cells, notably CSCs, primarily absorb their energy from glycolysis and lipolysis . Based on the previously published data, there is an inevitable relationship between the physiological bioactivity of stem cells and basal energy metabolism . Hexokinase and acetyl-CoA carboxylase (ACC) 1, the main enzymes regulating glycolysis and lipolysis, are at the center of attention and numerous agents were produced to control glycolysis and lipolysis by controlling their bioactivities . As a matter of fact, understanding the close relationship between glycolysis and lipolysis with EMT process could help us to forecast the CSCs behavior and tumor reaction against the distinct chemotherapeutic agent.
In this study, we isolated CSCs from the human cell line; SKOV3. To analyze the potential effect of glycolysis and lipolysis inhibition on the EMT of CSCs, we treated these cells with Lonidamine and TOFA and the expression of the key genes participating in EMT was monitored. In addition, endothelial differentiation of CSCs was evaluated by the expression of endothelial specific marker VE-cadherin under the inhibition of lipolysis and glycolysis. It seems that the results of the current experiment could shed a light on the potential role of glycolysis and lipolysis in the ability of CSCs to maintaining stemness feature and commitment toward mature cell type.
AP, MZH, JAZ performed the experiments. RR and MT conceived and designed the experiments in the manuscript. All authors read and approved the final manuscript.
We would like to thank all the colleagues in our research team for technical support.
The authors declare that they have no competing interests.
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This work was financially supported by the Tabriz University of Medical Sciences (Grant Numbers 95/75).
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