The Role of the Apoptotic Machinery in Tumor Suppression

Multicellular organisms have evolved processes to prevent abnormal proliferation or inappropriate tissue infiltration of cells, and these tumor suppressive mechanisms serve to prevent tissue hyperplasia, tumor development, and metastatic spread of tumors. These include potentially reversible processes such as cell cycle arrest and cellular senescence, as well as apoptotic cell death, which in contrast eliminates dangerous cells that may initiate tumor development. Tumor suppressive processes are organized as complex, extensive signaling networks, controlled by central “nodes.” These “nodes” are prominent tumor suppressors, such as P53 or PTEN, whose loss is responsible for the development of the majority of human cancers. In this review we discuss the processes by which some of these prominent tumor suppressors trigger apoptotic cell death and how this process protects us from cancer development.A malignant tumor is characterized by the ability to expand in an uncontrolled manner, destroy normal tissue architecture, and ultimately undergo metastatic spread (Hanahan and Weinberg 2000). Although the number of mutations required for neoplastic transformation may vary, all tumors are reliant on two critical mechanisms for their development; the activation of oncogenes that promote proliferation and survival of cancer cells, as well as the inactivation of tumor suppressor genes that normally repress development and growth of tumors (Hanahan and Weinberg 2000).Oncogenes can be activated via multiple mechanisms, including chromosomal translocations, deletions or insertions, as well as point mutations. One such example is the translocation between chromosomes 9 and 22 that is present in most cases of chronic myeloid leukemia. The juxtaposition of the BCR and c-ABL genes results in the production of an abnormal BCR-ABL fusion protein with constitutive kinase activity (Deininger et al. 2005). However, in other cancer-causing chromosomal translocations, such as the t8;14] translocation in Burkitt’s lymphoma, the coding sequence of the oncogene, c-MYC, is unchanged; rather its activation results from deregulated expression in B lymphoid cells as a consequence of its proximity to the IGH gene enhancer (Cory et al. 1987). Tumorigenesis promoted by deregulated kinase activity frequently results from the acquisition of point mutations. In this context, a single amino acid substitution can dramatically enhance kinase activity by preventing binding of negative regulators or “locking” the catalytic domain in the active conformation. This is exemplified by the BRAF(V600E) mutation frequently observed in melanoma or colon carcinoma (Poulikakos and Rosen 2011) and the activating mutations in EGF-R observed in lung adenocarcinoma (Sharma et al. 2007).Analogous to the activation of oncogenes, tumor suppressor genes can be inactivated through multiple mechanisms, including large-scale chromosomal alterations or point mutations. However, in most cases both alleles of the gene must be compromised to abolish gene function, unless the mutated protein can act in a dominant-negative fashion to block the activity of its wild-type counterpart.Multicellular organisms have evolved a plethora of mechanisms to restrain the growth or even eliminate aberrant cells—these processes can all function as tumor suppressors. Notably, of the attributes that cells must acquire to become cancerous (“hallmarks of cancer”) discussed by Hanahan and Weinberg (2000), several relate to escape from regulatory processes that would normally suppress tumor growth. They include cell cycle arrest, cellular senescence, and cell death; of these only cell death is irreversible, all others can (at least potentially) be reversed. In this review, we describe the mechanisms by which tumor suppressors that are disabled in a broad range and large fraction of cancers trigger cell death, and how components of the apoptotic machinery can themselves act as tumor suppressors.