Review
The causes of cancer revisited: “Mitochondrial malignancy” and ROS-induced oncogenic transformation – Why mitochondria are targets for cancer therapy

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Abstract

The role of oncoproteins and tumor suppressor proteins in promoting the malignant transformation of mammalian cells by affecting properties such as proliferative signalling, cell cycle regulation and altered adhesion is well established. Chemicals, viruses and radiation are also generally accepted as agents that commonly induce mutations in the genes encoding these cancer-causing proteins, thereby giving rise to cancer. However, more recent evidence indicates the importance of two additional key factors imposed on proliferating cells that are involved in transformation to malignancy and these are hypoxia and/or stressful conditions of nutrient deprivation (e.g. lack of glucose). These two additional triggers can initiate and promote the process of malignant transformation when a low percentage of cells overcome and escape cellular senescence. It is becoming apparent that hypoxia causes the progressive elevation in mitochondrial ROS production (chronic ROS) which 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.

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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