ReviewThe causes of cancer revisited: “Mitochondrial malignancy” and ROS-induced oncogenic transformation – Why mitochondria are targets for cancer therapy
Introduction
Cells in the body that retain normal growth control will eventually undergo the process of cellular senescence leading to turnover by their demise and replacement. By contrast, cells undergoing the process of oncogenic transformation continue to survive as immortalized cells leading to uncontrolled proliferation to form tumors. More recently a relationship between changes in mitochondrial function, associated production of reactive oxygen species (ROS) and its involvement in the process of cellular senescence has become increasingly clear (reviewed by Passos et al., 2009). However, the interplay between mitochondrial ROS production and the role of oncoproteins and tumor suppressors in modulating mitochondrial function to “promote” malignant cell transformation and avoid senescence has also become apparent.
The major nuclear encoded oncogenic proteins, MYC, p53, STAT-3 and RAS act either alone or in an integrated fashion to modulate gene expression involved in mitochondrial function, regulate the expression of genes encoding mitochondrial proteins, and by directly altering mitochondrial protein function inside cancer cells to promote cancer development. Thus, recent research has established that mitochondrial associated gene expression, whether nuclear derived or mitochondrially encoded is significantly different in cancer cells from that of normal cells and helps to explain the changes in mitochondrial function emerging in developing cancer cells. Thus, it is apparent that cancer cell emergence during the process of malignant transformation is critically dependent on the interactions of key oncogenes and tumor suppressor genes and their encoded products with progressive changes in mitochondrial function and ROS production which enable cells to survive the normal process of senescence and induction of oxidative damage-mediated cell death, thereby escaping elimination to emerge as tumor-initiating cells. The evidence for these conclusions is reviewed here.
Section snippets
The importance of ROS for cell growth signal stimulation and survival to overcome senescence – a role in carcinogenesis
In mammalian cells, mitochondria are one of the major sources of ROS which has an important role in diverse events such as cellular proliferation, differentiation and migration (reviewed in Rhee, 2006, Hancock, 2009). Understanding the role of ROS in cellular function has now advanced to the stage where cellular “redox” signalling is accepted to be involved in regulating normal processes and disease progression, including angiogenesis, oxidative stress, aging, and cancer. In particular,
Hypoxia and low glucose drive carcinogenesis via malignant mitochondrial ROS production and increased biogenesis
Accumulating evidence indicates that oxidative stress and ROS, in particular, play an important role in carcinogenesis, its development and progression and higher levels of ROS are commonly observed in cancer cells (reviewed in López-Lázaro, 2007a, López-Lázaro, 2007b, Fruehauf and Meyskens, 2007). During the process of malignant cell transformation, the early initiating events and the role of mitochondria are becoming increasingly apparent. Prolonged hypoxia and glucose deprivation are key
Mitochondrial genome changes in cancer
The hundreds of mitochondrial proteins include a subset of 13 encoded by the mtDNA (Fig. 5) with the remaining proteins encoded by nuclear DNA. The mitochondrial genome in human cells is extremely small (16,569 bp) compared to the nuclear DNA although every mitochondrion contains between 2 and 20 copies of mtDNA and the copy number of mitochondrial genomes per cell ranges from several hundreds to more than 10,000 depending on the cell type (typically around 1000 mitochondria per cell). The
Implications for cancer therapy and why mitochondria provide excellent targets
A general property of oncogene transformed cells with dysfunctional mitochondria and associated increased ROS production is that as a consequence of this state they will exhibit a lower threshold of sensitivity to ROS-induced apoptosis as a means for eliminating them. Increasingly, and in line with the evidence already presented, it is highly likely for cancer cells (relative to normal cells) to have altered mitochondrial electron transport chains (ETC) that are more efficient in ROS (O2− and H2
Concluding discussion
The summary of emerging evidence in this review strongly supports a key role played by mitochondria in oncogenesis and the process of malignant cellular transformation. Interestingly, the oncoproteins p53, MYC and RAS are all able to increase TFAM levels to promote mtDNA biogenesis and increased mitochondrial numbers in cancer cells. Another common theme emerging is that mitochondrial metabolism is altered and respiration partially uncoupled from ATP synthesis (OxPhos) with elevated and
Acknowledgements
The work of Sara Rodríguez-Enríquez and Rafael Moreno-Sánchez was partially supported by grants from CONACyT-México No. 80534 and 107183 and Instituto de Ciencia y Tecnología del Distrito Federal, México, No. PICS08-5. Jiri Neuzil and Stephen J. Ralph were supported by grants from the Queensland Cancer Council, Australia, the National Breast Cancer Foundation and Australian Research Council. The authors acknowledge the helpful comments of Prof. R.K. Ralph made during the preparation of this
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