Mitochondria and Cancer

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Given the important roles mitochondria play in cellular energy metabolism, free radical formation and PCD, defects in mitochondrial function are suspected to contribute to the development and progression of cancer and to resistance to therapy (Bettaieb et al., 2003; Brenner et al., 2003; Costantini et al., 2000; Debatin et al., 2002; Hersey and Zhang, 2003; Jaattela, 2004; Kasibhatla and Tseng, 2003; Kim et al., 2004). Defective apoptosis is one of the hallmarks of tumorigenicity and is implicated in multiple stages of tumor progression (Burns and El-Deiry, 2003; Hanahan and Weinberg, 2000; Ozoren and El-Deiry, 2003). Furthermore, the ability of tumor cells to escape apoptosis plays a key role in promoting resistance to conventional chemotherapy and radiation therapy (Abe et al., 2000; Barnhart et al., 2004; Daniel et al., 2001; El-Deiry, 1997; Thompson, 1995; Zornig et al., 2001).

A link between mitochondria and cancer progression was suggested over half a century ago when Warburg reported the role of mitochondria in cellular energy metabolism. This phenomenon was coined the "Warburg effect." The Warburg effect suggested that the development of an injury to the respiratory machinery is an important event in carcinogenesis (Warburg, 1951). This injury results in compensatory increases in glycolytic ATP production to fulfill the energy needs of tumor cells. Since then, preferential reliance on glycolysis over the oxidative metabolism has been shown to correlate with tumor progression in several types of cancer (Semenza et al., 2001). Since the initial report of the Warburg effect, a number of cancer-related mitochondrial defects have also been identified (Brenner et al., 2003; Carew and Huang, 2002; Debatin et al., 2002; Jaattela, 2004). These defects include altered expression and activity of respiratory chain subunits and glycolytic enzymes, changes in oxidation of NADH-linked substrates and mutations in mitochondrial DNA. Thus, the differences in energy metabolism between normal cells and cancer cells constitute a biochemical basis for the development of therapeutic strategies that might selectively kill cancer cells in their compromised respiratory state.

Furthermore, dysregulation of members of the Bcl-2 family has been detected in a variety of malignancies, especially hematological cancers. Bcl-2 itself was originally discovered as an oncogene in B cell lymphoma Danial and Korsmeyer, 2004. Additionally, overexpression of Bcl-2 has been detected in AML and non-Hodgkin's lymphomas. Dysregulation of other Bcl-2 family proteins have also been detected in other cancers; for example, increased expression of Mcl-1 has been detected in relapsed AML and multiple myeloma. Increased expression levels and mutations in the promoter of the mcl-1 gene have also been observed in chronic lymphoblastic leukemias. These studies reiterate that changes to the mitochondrial-associated proteins, mainly members of the Bcl-2 family, are directly involved in tumor progression.

Additionally, there is some evidence that alterations in the mitochondrial DNA could also be involved in cancer progression. Besides hosting hundreds of nuclear encoded proteins, mitochondria have their own DNA that encodes 13 mitochon-drial proteins (Schatz, 1995; Singh et al., 1999). Mutations in mtDNA could occur during oxidative phosphorylation involving ROS. Investigations of human bladder, lung, neck, and head primary tumors revealed a high percentage of mtDNA mutation (~50%) in these tumors (Fliss et al., 2000). These observations suggest a link between cancer development and mitochondrial dysfunction; however, they do not present a clear answer to whether mitochondrial DNA mutation is simply a result, or rather the cause, of alterations in PCD.

Mitochondria also play an important role in resistance to chemotherapy and radiation therapy. Since mitochondria are integrators of apoptotic signaling pathways, induction of apoptosis in many cell types leads to the induction of MMP (Brenner et al., 2003; Kroemer, 2003). MMP defines the point of no return in most PCD pathways and is regulated by pre-mitochondrial signal transduction pathways. These pathways involve caspase-dependent and caspase-independent mechanisms, members of the Bcl-2 family of proteins and changes in the composition of mitochondrial membranes (Bettaieb et al., 2003; Brenner et al., 2003; Green and Kroemer, 2004; Kim et al., 2004; Kroemer, 2003; Kuwana et al., 1998; Newmeyer and Ferguson-Miller, 2003; Peter and Krammer, 1998; Ravagnan et al., 2002; Sorice et al., 2004; Waterhouse et al., 2001; Zamzami and Kroemer, 2001). In response to MMP, proapoptotic factors are released into the cytosol to trigger the execution of cell death. This is likely due to the opening of protein channels such as the VDAC. Under pathological conditions, cancer cells escape from apoptosis and/or become resistant to treatment by affecting MMP (Bettaieb et al., 2003; Debatin et al., 2002; Hersey and Zhang, 2003; Kim et al.,

2004). Therefore, overcoming abnormalities in tumor cells that suppress MMP could lead to therapeutic targets by generating a potent proapoptotic stimulus. Additionally, since MMP is an early event in apoptosis, strategies to detect this process can be useful in assessing the response to chemotherapy.

Mutations in mtDNA have been implicated in the cellular response to chemotherapy. For example, Singh et al. (1999) examined the response of a tumor cell line lacking mitochondrial DNA to several anticancer drugs, including adriamy-cin (a DNA-interacting drug widely used in chemotherapy for its role in binding DNA and stopping the process of replication). Cancer cells lacking mtDNA showed great chemotherapy resistance, indicating an important role of the mito-chondrial genome in regulating the cellular response to therapeutic agents. Similar findings were also reported in A549 non-small-cell lung cancer cell lines and their rho0 derivatives in which mitochondrial DNA has been eradicated (Lo et al., 2005). The parental cell line showed increased sensitivity to chemotherapy when compared with the mtDNA-compromised derivative cell line. Notably, the restoration of mtDNA restored chemosensitivity of the resistant cell line (Lo et al., 2005).

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