Why mitochondria are excellent targets for cancer therapy (original) (raw)
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Molecular Aspects of Medicine, 2010
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m a m over time leads to stabilization of cells via increased HIF-2alpha expression, enabling cells to survive with sustained levels of elevated ROS. In cells under hypoxia and/or low glucose, DNA mismatch repair processes are repressed by HIF-2alpha and they continually accumulate mitochondrial ROS-induced oxidative DNA damage and increasing numbers of mutations driving the malignant transformation process. Recent evidence also indicates that the resulting mutated cancer-causing proteins feedback to amplify the process by directly affecting mitochondrial function in combinatorial ways that intersect to play a major role in promoting a vicious spiral of malignant cell transformation. Consequently, many malignant processes involve periods of increased mitochondrial ROS production when a few cells survive the more common process of oxidative damage induced cell senescence and death. The few cells escaping elimination emerge with oncogenic mutations and survive to become immortalized tumors. This review focuses on evidence highlighting the role of mitochondria as drivers of elevated ROS production during malignant transformation and hence, their potential as targets for cancer therapy. The review is organized into five main sections concerning different aspects of ''mitochondrial malignancy". The first concerns the functions of mitochondrial ROS and its importance as a pacesetter for cell growth versus senescence and death. The second considers the available evidence that cellular stress in the form of hypoxic and/or hypoglycaemic conditions represent two of the major triggering events for cancer and how oncoproteins reinforce this process by altering gene expression to bring about a common set of changes in mitochondrial function and activity in cancer cells. The third section presents evidence that oncoproteins and tumor suppressor proteins physically localize to the mitochondria in cancer cells where they directly regulate malignant mitochondrial programs, including apoptosis. The fourth section covers common mutational changes in the mitochondrial genome as they relate to malignancy and the relationship to the other three areas. The last section concerns the relevance of these findings, their importance and significance for novel targeted approaches to anti-cancer therapy and selective triggering in cancer cells of the mitochondrial apoptotic pathway.
Hypoxic enlarged mitochondria protect cancer cells from apoptotic stimuli
Journal of Cellular Physiology, 2009
It is well established that cells exposed to the limiting oxygen microenvironment (hypoxia) of tumors acquire resistance to chemotherapy, through mechanisms not fully understood. We noted that a large number of cell lines showed protection from apoptotic stimuli, staurosporine, or etoposide, when exposed to long-term hypoxia (72 h). In addition, these cells had unusual enlarged mitochondria that were induced in a HIF-1-dependent manner. Enlarged mitochondria were functional as they conserved their transmembrane potential and ATP production. Here we reveal that mitochondria of hypoxia-induced chemotherapy-resistant cells undergo a HIF-1-dependent and mitofusin-1-mediated change in morphology from a tubular network to an enlarged phenotype. An imbalance in mitochondrial fusion/ fission occurs since silencing of not only the mitochondrial fusion protein mitofusin 1 but also BNIP3 and BNIP3L, two mitochondrial HIF-targeted genes, reestablished a tubular morphology. Hypoxic cells were insensitive to staurosporine-and etoposide-induced cell death, but the silencing of mitofusin, BNIP3, and BNIP3L restored sensitivity. Our results demonstrate that some cancer cells have developed yet another way to evade apoptosis in hypoxia, by inducing mitochondrial fusion and targeting BNIP3 and BNIP3L to mitochondrial membranes, thereby giving these cells a selective growth advantage.
The tumor suppressor function of mitochondria: Translation into the clinics
Biochimica Et Biophysica Acta-molecular Basis of Disease, 2009
Recently, the inevitable metabolic reprogramming experienced by cancer cells as a result of the onset of cellular proliferation has been added to the list of hallmarks of the cancer cell phenotype. Proliferation is bound to the synchronous fluctuation of cycles of an increased glycolysis concurrent with a restrained oxidative phosphorylation.
Mitochondria and the hallmarks of cancer
FEBS Journal, 2015
Mitochondria have been traditionally viewed as the powerhouse of the cell due to their major role in the generation of ATP. More recently, mitochondria have also been demonstrated to have key roles in a variety of other processes such as apoptotic cell death and inflammation. Here we review the different ways in which mitochondrial functions impact on cancer. While cancer is comprised of diverse types, distinct hallmarks have been defined that are applicable to most cancer types. We provide an overview of how mitochondria impact on specific hallmarks; these include evasion of cell death, deregulated bioenergetics, genome instability, tumour promoting inflammation and metastasis. In addition to discussing the underlying mitochondrial roles in each of these processes, we also highlight the considerable promise of targeting mitochondrial functions in order to improve cancer treatment.
Mitochondria and cancer: past, present, and future
BioMed research international, 2013
The area of mitochondrial genomics has undergone unprecedented growth over the past several years. With the advent of the age of omics, investigations have reached beyond the nucleus to encompass the close biological communication and finely coordinated interactions between mitochondria and their nuclear cell mate. Application of this holistic approach, to all metabolic interactions within the cell, is providing a more complete understanding of the molecular transformation of the cell from normal to malignant behavior, before histopathological indications are evident. In this review the surging momentum in mitochondrial science, as it relates to cancer, is described in three progressive perspectives: (1) Past: the historical contributions to current directions of research; (2) Present: Contemporary findings, results and approaches to mitochondria and cancer, including the role of next generation sequencing and proteomics; (3) FUTURE: Based on the present body of knowledge, the poten...
Cancer and mitochondrial function.
Investigaciones respecto al cáncer y la función mitocondriaL- Unicauca , 2018
Se ha descrito que algunas alteraciones del metabolismo están asociadas con la pérdida de función mitocondrial en células tumorales. Aún se discute si tal pérdida se evidencia en la función o si la célula brinda máxima estabilidad a sus funciones, se requieren más estudios para conocer el comportamiento del cáncer en la mitocondria. Cuando tiene limitación de oxígeno y mutaciones en oncogenes, genes supresores de tumor y enzimas de la vía glucolítica o del metabolismo oxidativo mitocondrial, la célula tumoral permite la formación de un cáncer agresivo. Este artículo es producto de la revisión bibliográfica de la evidencia científica que se ha presentado en las últimas investigaciones respecto al cáncer y la función mitocondrial. DOI: https://doi.org/10.15446/.v66n1.59898 Sofía Isabel Freyre-Bernal, Jhan Sebastián Saavedra-Torres, Luisa Fernanda Zúñiga-Cerón, Wilmer Jair Díaz -Córdoba, María Virginia Pinzón-Fernández. Cancer and mitochondrial function. (El cáncer en la función mitocondrial) Rev. Fac. Med., Volume 66, Issue 1, p. 83-86, 2018. eISSN 2357-3848. Print ISSN 0120-0011.
Virchows Archiv, 2009
The authors review the role played by mutations in mitochondrial DNA and in nuclear genes encoding mitochondrial proteins in cancer development, with an emphasis on the alterations of the oxidative phosphorylation system and glycolysis.
Altered Mitochondrial Signalling and Metabolism in Cancer
Frontiers in Oncology, 2017
Mitochondria being the central organelle for metabolism and other cell signalling pathways have remained the topic of interest to tumour biologists. In spite of the wide acceptance of Warburg's hypothesis, role of mitochondrial metabolism in cancer is still unclear. Uncontrolled growth and proliferation, hallmarks of tumour cells, are maintained when the cells adapt to metabolic reprogramming with the help of altered metabolism of mitochondria. This review has focussed on different aspects of mitochondrial metabolism and interrelated signalling pathways which have been found to be modified in cancer.
Metabolic sculpting of the mitochondria, cell signaling and the cancer phenotype
Translational cancer research, 2017
An understanding of metabolic pathways, most notably abnormal metabolite states that agitate normal physiology, is fundamental to the approach to all disease oriented research and can have broad impact on our understanding of cancer treatment. Recent research implicates mitochondrial metabolism in the induction of widespread changes in macrophage gene expression and alterations in the anti/pro-inflammatory cytokine generation. We examine the role of metabolic gene signaling in the recent work of Mills et al., in the framework of the cancer phenotype. A shift in the rate of mitochondrial succinate oxidation modifies the steady state levels of superoxide/hydrogen peroxide, which in turn modulates the levels of active hypoxia inducible factor 1 alpha subunit (HIF-1α), and can result in 'chemical hypoxia'. Chemical hypoxia occurs when the hypoxia signaling pathways are active, at non-hypoxic oxygen levels. In this paper, we examine the work of Mills et al., and provide data for gliomas that further supports the hypothesis that an altered metabolism changes in the tumor microenvironment. This alteration can distinctly drive the cell to a set of interconnected molecular pathways, with both 2-oxoglutarate and succinate levels acting as regulators.