Energy Metabolic Plasticity of Colorectal Cancer Cells as a Determinant of Tumor Growth and Metastasis

Reinsalu, Leenu; Puurand, Marju; Chekulayev, Vladimir; Miller, Sten; Shevchuk, Igor; Tepp, Kersti; Rebane-Klemm, Egle; Timohhina, Natalja; Terasmaa, Anton; Käämbre, Tuuli

doi:10.3389/fonc.2021.698951

Cited by 7 publications

(5 citation statements)

References 130 publications

(198 reference statements)

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“…BZD is an antagonist of TSPO ( 30 ), whose application decreased TSPO expression ( 31 ), which proved that Rem reduced TSPO expression and inhibited the proliferation of HCT116, as well as the expression of CRC-markers, CEA and CA19-9, and promoted the apoptosis of HCT116. TSPO, like VDAC, is also a mitochondrial protein ( 32 , 33 ). String online database analysis found that TSPO can interact with a variety of VDAC molecules, and the regulation of TSPO expression can affect VDAC expression in HCT116 (Result 4).…”

Section: Discussionmentioning

confidence: 99%

Inhibiting the Proliferation of Colorectal Cancer Cells by Reducing TSPO/VDAC Expression

Liu

Wang

Yang

2023

ijph

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Background: We aimed to explore the mechanism of the effect of remimazolam (Rem) on the proliferation of colorectal cancer (CRC) cells with CRC as a disease context. Methods: Translocation protein (TSPO) expression in CRC was determined by Western blotting and qRT-PCR in the Second Affiliated Hospital of Qiqihar Medical University from March 2019 to February 2022. TSPO-interacting proteins were predicted through string database. The proliferation was measured by CCK-8 and 5-ethynyl-2-deoxyuridine (EDU). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) and clonal colony on cells were formed to screen for the optimal concentration of Rem and to detect the viability. The expression of apoptosis-related proteins, Bcl-2 and P53, was determined by qRT-PCR and Western blotting. The effect of Rem on the expression of tumor markers, CEA and CA19-9, in CRC was examined through ELISA. Results: TSPO expression in CRC tissues and cells was higher than that in ANT samples and normal intestinal epithelial cells. Over-expression of TSPO promoted the proliferation of HCT116 and the expression of tumor markers CEA and CA19-9 and inhibited the apoptosis of HCT116. Interference with TSPO inhibited the proliferation of HCT116 and the expression of CEA and CA19-9 and promoted the apoptosis of HCT116. 1 μg/mL Rem could inhibit the viability of HCT116, the proliferation of HCT116 and the expression of CEA and CA19-9, and improve the apoptosis of HCT116. TSPO could interact with VDAC and affect its protein expression, and Rem could inhibit the proliferation and the expression of CEA and CA19-9 through the TSPO/VDAC pathway, to promote its apoptosis. Conclusion: Rem affects the proliferation of CRC cells by inhibiting the TSPO/VDAC pathway.

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Section: Discussionmentioning

confidence: 99%

Inhibiting the Proliferation of Colorectal Cancer Cells by Reducing TSPO/VDAC Expression

Liu

Wang

Yang

2023

ijph

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“…Hexokinases (HKs), which mediate the utilization of glucose, are present in the cytoplasm where they phosphorylate intracellular glucose, the first rate‐limiting step of glycolysis 48,49 . Of the four HK subtypes (encoded by different genes), HK1 is expressed in normal tissues while HK2 is highly expressed in cancer cells and facilitates chemoresistance and metastasis of hepatocellular, colorectal, lung, gastric, melanoma, and ovarian cancers 50–57 . HK2 can translocate from the cytoplasm to the outer mitochondrial membrane and interact with the voltage‐dependent anion channel to promote resistance to chemotherapy by inhibiting apoptosis.…”

Section: Cancer Metabolism In Metastatic Cellsmentioning

confidence: 99%

“…48,49 Of the four HK subtypes (encoded by different genes), HK1 is expressed in normal tissues while HK2 is highly expressed in cancer cells and facilitates chemoresistance and metastasis of hepatocellular, colorectal, lung, gastric, melanoma, and ovarian cancers. [50][51][52][53][54][55][56][57] HK2 can translocate from the cytoplasm to the outer mitochondrial membrane and interact with the voltagedependent anion channel to promote resistance to chemotherapy by inhibiting apoptosis. Mitochondrial-associated HK2 (Mito-HK2) is also in close proximity to mitochondrial ATP production by ATP synthase and may prevent cell death by multiple mechanisms.…”

Section: Cancer Metabolism In Metastatic Cellsmentioning

confidence: 99%

Targeting mitochondrial metabolism for metastatic cancer therapy

Passaniti

Kim

Polster

et al. 2022

Molecular Carcinogenesis

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Primary tumors evolve metabolic mechanisms favoring glycolysis for adenosine triphosphate (ATP) generation and antioxidant defenses. In contrast, metastatic cells frequently depend on mitochondrial respiration and oxidative phosphorylation (OxPhos). This reliance of metastatic cells on OxPhos can be exploited using drugs that target mitochondrial metabolism. Therefore, therapeutic agents that act via diverse mechanisms, including the activation of signaling pathways that promote the production of reactive oxygen species (ROS) and/or a reduction in antioxidant defenses may elevate oxidative stress and inhibit tumor cell survival. In this review, we will provide (1) a mechanistic analysis of function‐selective extracellular signal‐regulated kinase‐1/2 (ERK1/2) inhibitors that inhibit cancer cells through enhanced ROS, (2) a review of the role of mitochondrial ATP synthase in redox regulation and drug resistance, (3) a rationale for inhibiting ERK signaling and mitochondrial OxPhos toward the therapeutic goal of reducing tumor metastasis and treatment resistance. Recent reports from our laboratories using metastatic melanoma and breast cancer models have shown the preclinical efficacy of novel and rationally designed therapeutic agents that target ERK1/2 signaling and mitochondrial ATP synthase, which modulate ROS events that may prevent or treat metastatic cancer. These findings and those of others suggest that targeting a tumor's metabolic requirements and vulnerabilities may inhibit metastatic pathways and tumor growth. Approaches that exploit the ability of therapeutic agents to alter oxidative balance in tumor cells may be selective for cancer cells and may ultimately have an impact on clinical efficacy and safety. Elucidating the translational potential of metabolic targeting could lead to the discovery of new approaches for treatment of metastatic cancer.

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“…Interestingly, in cancerous non-beating HL-1 cells of cardiac phenotype, where both β2 tubulin isoform and mtCK are absent, the apparent K m for exogenous ADP is low [37]. Some cancer cells show increased β3 tubulin expression [38] which may play a role in regulating VDAC activity, but more studies are needed to confirm its overexpression in HL-1. A hypothetical model has been proposed which suggests that hexokinase-II replaces β2 tubulin in binding to VDAC and switch the energy transfer to the Warburg-Pedersen pathway [39][40][41].…”

Section: (A) Cytoskeletal Regulation Of Mitochondria In Cardiomyocytesmentioning

confidence: 99%

How cytoskeletal proteins regulate mitochondrial energetics in cell physiology and diseases

Solomon

Rajendran

Rostovtseva

et al. 2022

Phil. Trans. R. Soc. B

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Mitochondria are ubiquitous organelles that play a pivotal role in the supply of energy through the production of adenosine triphosphate in all eukaryotic cells. The importance of mitochondria in cells is demonstrated in the poor survival outcomes observed in patients with defects in mitochondrial gene or RNA expression. Studies have identified that mitochondria are influenced by the cell's cytoskeletal environment. This is evident in pathological conditions such as cardiomyopathy where the cytoskeleton is in disarray and leads to alterations in mitochondrial oxygen consumption and electron transport. In cancer, reorganization of the actin cytoskeleton is critical for trans-differentiation of epithelial-like cells into motile mesenchymal-like cells that promotes cancer progression. The cytoskeleton is critical to the shape and elongation of neurons, facilitating communication during development and nerve signalling. Although it is recognized that cytoskeletal proteins physically tether mitochondria, it is not well understood how cytoskeletal proteins alter mitochondrial function. Since end-stage disease frequently involves poor energy production, understanding the role of the cytoskeleton in the progression of chronic pathology may enable the development of therapeutics to improve energy production and consumption and slow disease progression. This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.

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Energy Metabolic Plasticity of Colorectal Cancer Cells as a Determinant of Tumor Growth and Metastasis

Cited by 7 publications

References 130 publications

Inhibiting the Proliferation of Colorectal Cancer Cells by Reducing TSPO/VDAC Expression

Inhibiting the Proliferation of Colorectal Cancer Cells by Reducing TSPO/VDAC Expression

Targeting mitochondrial metabolism for metastatic cancer therapy

How cytoskeletal proteins regulate mitochondrial energetics in cell physiology and diseases

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