Mitochondria targeting and its consequences for cell death in neuroblastoma
Author: Valter, Kadri
Date: 2019-01-18
Location: Petrénsalen, Nobels väg 12b, Karolinska Institutet, Solna
Time: 09.30
Department: Institutet för miljömedicin / Institute of Environmental Medicine
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Thesis (1.614Mb)
Abstract
Mitochondria are one of the central regulators of several physiological and pathological processes. For instance, homeostatic glycolysis, citric acid cycle, and oxidative phosphorylation are all regulated by mitochondria. In addition, these organelles play a pivotal role in apoptosis, a process of programmed cell death. In detail, the permeabilization of the outer mitochondrial membrane and the release of pro-apoptotic proteins from the intermembrane space are considered as an initiating and the no return step of apoptosis. Therefore, apoptosis induction and targeting mitochondria of cancer cells is a promising strategy for tumor cell elimination. During the studies of this PhD project mitochondria targeting and its consequences for cell death in neuroblastoma (NB) were investigated.
In Paper I we demonstrated how low doses of the mitochondrial Complex II inhibitor thenoyltrifluoroacetone (TTFA) can sensitize a panel of chemoresistant NB cells for cisplatin treatment. Increase in cell death was due to TTFAs specific inhibition of the ubiquinonebinding site of succinate dehydrogenase (SDH) that led to the formation of reactive oxygen species (ROS). Excessive ROS production resulted in the cytochrome c release from the intermembrane space of mitochondria and activation of apoptosis. However, the coadministration of TTFA and cisplatin increased cell death only in NB cell lines with functionally active SDH. These results revealed how mitochondria targeting can be used to raise treatment efficacy, but previous testing of SDH activity is needed for successful outcome.
Many of therapeutic drugs damage DNA, but their ability to target mitochondria is unknown. The effect of conventionally used chemotherapeutic drugs on mitochondria was tested in Paper II. Obtained results revealed etoposide-triggered suppression of Complex I respiration. Blockage of the electron chain led to the ROS formation, which did not induce apoptosis. However, cell death was detected after removal of glutamine, a precursor of the antioxidant glutathione. Therefore, etoposide also sensitizes mitochondria and can direct the mitochondrial membrane properties to apoptosis. Several tumors, such as NB, are dependent on glutamine and targeting glutamine metabolism offers a rationale for treatment improvement. The effect of glutamine withdrawal on anticancer drug treatment of NB cells was studied in Paper III. We discovered a contrasting effect of drugs in glutamine deprived environment. Glutamine removal inhibited etoposide-induced, but significantly increased cisplatin-induced apoptosis, suggesting the activation of distinct mechanisms. Nevertheless, targeting glutamine metabolism could be considered as part of anticancer therapy, but further studies to understand the mechanism of this finding are needed.
Taken together, the findings of this PhD thesis have given new insights into mitochondria targeting for tumor cell elimination. We found new sensitizing effects of TTFA and etoposide that target respiratory chain complexes. Furthermore, the PhD project elucidated the role of glutamine metabolism in the outcome of NB treatment, which can be used as a basis for further studies.
In Paper I we demonstrated how low doses of the mitochondrial Complex II inhibitor thenoyltrifluoroacetone (TTFA) can sensitize a panel of chemoresistant NB cells for cisplatin treatment. Increase in cell death was due to TTFAs specific inhibition of the ubiquinonebinding site of succinate dehydrogenase (SDH) that led to the formation of reactive oxygen species (ROS). Excessive ROS production resulted in the cytochrome c release from the intermembrane space of mitochondria and activation of apoptosis. However, the coadministration of TTFA and cisplatin increased cell death only in NB cell lines with functionally active SDH. These results revealed how mitochondria targeting can be used to raise treatment efficacy, but previous testing of SDH activity is needed for successful outcome.
Many of therapeutic drugs damage DNA, but their ability to target mitochondria is unknown. The effect of conventionally used chemotherapeutic drugs on mitochondria was tested in Paper II. Obtained results revealed etoposide-triggered suppression of Complex I respiration. Blockage of the electron chain led to the ROS formation, which did not induce apoptosis. However, cell death was detected after removal of glutamine, a precursor of the antioxidant glutathione. Therefore, etoposide also sensitizes mitochondria and can direct the mitochondrial membrane properties to apoptosis. Several tumors, such as NB, are dependent on glutamine and targeting glutamine metabolism offers a rationale for treatment improvement. The effect of glutamine withdrawal on anticancer drug treatment of NB cells was studied in Paper III. We discovered a contrasting effect of drugs in glutamine deprived environment. Glutamine removal inhibited etoposide-induced, but significantly increased cisplatin-induced apoptosis, suggesting the activation of distinct mechanisms. Nevertheless, targeting glutamine metabolism could be considered as part of anticancer therapy, but further studies to understand the mechanism of this finding are needed.
Taken together, the findings of this PhD thesis have given new insights into mitochondria targeting for tumor cell elimination. We found new sensitizing effects of TTFA and etoposide that target respiratory chain complexes. Furthermore, the PhD project elucidated the role of glutamine metabolism in the outcome of NB treatment, which can be used as a basis for further studies.
List of papers:
I. Kruspig B, Valter K, Skender B, Zhivotovsky B, Gogvadze V. (2016). Targeting succinate:ubiquinone reductase potentiates the efficacy of anticancer therapy. Biochimica et Biophysica Acta. 1863: 2065-2071.
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II. Valter K, Maximchik P, Zhivotovsky B, Gogvadze V. Distinct effects of etoposide on glutamine-addicted neuroblastoma. [Submitted]
III. Valter K, Chen L, Kruspig B, Maximchik P, Cui H, Zhivotovsky B, Gogvadze V. (2017). Contrasting effects of glutamine deprivation on apoptosis induced by conventionally used anticancer drugs. Biochimica et Biophysica Acta. 1864: 498-506.
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I. Kruspig B, Valter K, Skender B, Zhivotovsky B, Gogvadze V. (2016). Targeting succinate:ubiquinone reductase potentiates the efficacy of anticancer therapy. Biochimica et Biophysica Acta. 1863: 2065-2071.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Valter K, Maximchik P, Zhivotovsky B, Gogvadze V. Distinct effects of etoposide on glutamine-addicted neuroblastoma. [Submitted]
III. Valter K, Chen L, Kruspig B, Maximchik P, Cui H, Zhivotovsky B, Gogvadze V. (2017). Contrasting effects of glutamine deprivation on apoptosis induced by conventionally used anticancer drugs. Biochimica et Biophysica Acta. 1864: 498-506.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Gogvadze, Vladimir
Co-supervisor: Zhivotovsky, Boris
Issue date: 2018-12-14
Rights:
Publication year: 2018
ISBN: 978-91-7831-273-3
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