Mitochondrial apoptosis: killing cancer using the enemy within
the ultimate goal of improving cancer treatment. Mitochondria, cell death and cancer. Apoptosis requires caspase protease activity, leading to widespread. Cell death also plays key roles in the treatment of cancer. Although we will restrict our discussion to mitochondrial apoptosis, it is important to note that .. Gillet G. Non-apoptotic roles of Bcl-2 family: the calcium connection. Hence, many of the mitochondrial gene mutations in cancer are intimately as PPID), which are regulatory, in association with the BCL-2 pro- and anti-apoptotic .
To date, at least 15 Bcl-2 family member proteins have been identified in mammalian cells, including proteins that promote apoptosis and those that prevent apoptosis In addition to Bcl-2, Bcl-xL is a potent death suppressor that is upregulated in some tumor types Conversely, Bax is a death promoter that is inactivated in certain types of colon cancer and in hematopoietic malignancies 13 Byp53 was clearly established as a checkpoint protein involved in cell-cycle arrest and maintaining genomic integrity following DNA damage.
However, p53 could induce apoptosis when overexpressed in a myeloid leukemia cell line, suggesting that p53 might also regulate cell survival Studies using p53 knockout mice demonstrated that endogenous p53 could participate in apoptosis: Hence, the role of p53 in apoptosis was indirectly linked to DNA damage and could be stimulus- radiation and tissue-specific thymocytes.
It is now known that other stimuli can activate p53 to promote apoptosis, including hypoxia and mitogenic oncogenes see below. Moreover, several upstream and downstream components of the p53 pathway e.
Mdm-2, ARF and Bax are mutated in human tumors Although the initial studies on Bcl-2 and p53 established the importance of apoptosis in carcinogenesis, it is now clear that mutations in many cancer-related genes can disrupt apoptosis. One critical pathway involves signaling through PI-3 kinase 20which can be activated by Ras and is downregulated by the PTEN tumor suppressor Ras activation and PTEN loss are common in human tumors.
Studies using transgenic and knockout mice provide direct evidence that disruption of apoptosis can promote tumor development. In addition to the lymphomas 10bcl-2 transgenes accelerate SV40 large T antigen-induced mammary carcinogenesis In many cases, p53 loss is associated with reduced apoptosis in situ. Additionally, mouse studies reveal the crucial role of extracellular survival factors in supporting tumor progression.
For example, large T antigen-induced pancreatic tumors require the upregulation of insulin-like growth factor 2 IGF-2 for progression to carcinomas—in fact, tumors arising in IGF-2 animals remain hyperplastic and display excessive apoptosis Moreover, inactivation of PTEN promotes tumorigenesis and cell survival when disrupted in mice 21and disruption of the pro-apoptotic bax gene accelerates brain and mammary tumorigenesis in large T antigen transgenic mice 25 Because molecules that regulate apoptosis can have other activities, it is often difficult to demonstrate that mutations in tumors actually confer a survival advantage.
For example, p53 can promote apoptosis, cell-cycle arrest and senescence such that loss of p53 function increases viability, chromosomal instability and cellular lifespan. However, compelling evidence indicates its apoptotic activity is important in tumor suppression. First, marked decreases in apoptosis correlate with the occurrence of p53 mutations in some transgenic mice 23 and in clonal progression of Wilms' tumor Second, disruption of several p53 effectors in apoptosis e. In colon cancer, bax and p53 mutations appear mutually exclusive, consistent with a pathway relationship In contrast, p21, which is essential for pmediated arrest, is rarely mutated in human tumors Finally, some tumor-derived p53 mutants remain capable of promoting cell-cycle arrest while losing their apoptotic potential 32 Nevertheless, these data do not imply that the other p53 activities are dispensible for tumor suppression; rather, they simply argue that its apoptotic activity is important.
Apoptosis in cancer | Carcinogenesis | Oxford Academic
What triggers apoptosis during tumor development? A variety of signals appear important. Internal imbalances can also trigger apoptosis, including DNA damage produced by cell-cycle checkpoint defects or exogenous toxinstelomere malfunction and inappropriate proliferative signals produced by oncogenic mutations.
In contrast, other stimuli involve true pro-apoptotic factors; as an example, many forms of cellular stress can activate p53, which promotes apoptosis through pro-apoptotic molecules like Bax 2528 For example, in the skin, excessive exposure to UV radiation induces apoptosis, which presumably serves to eliminate heavily damaged cells.
UV radiation induces apoptosis, and loss of p53 function leads to the survival of these damaged cells thereby initiating tumor development Other apoptotic triggers are important in tumor progression. As developing tumors outgrow their blood supply, they encounter hypoxia low oxygenwhich can activate p53 to promote apoptosis Cells acquiring apoptosis defects e. Similarly, as developing tumor cells undergo repeated divisions, telomeres are shortened until some malfunction triggers either senescence or apoptosis.
Like hypoxia, p53 is required for apoptosis induced by telomere malfunction; thus p53 mutant cells survive this response and are genomically unstable Indeed, suppression of the apoptotic response to telomere malfunction may explain why combined loss of telomerase and p53 stimulates tumor development These studies may explain why p53 mutations are usually late events in tumor development—a cell acquiring a p53 mutation might not have a selective advantage until the developing tumor encounters hypoxic conditions or achieves sufficient telomere erosion.
Disruption of apoptosis may also contribute to tumor metastasis. To metastasize, a tumor cell must acquire the ability to survive in the bloodstream and invade a foreign tissue. Normally, this process is prevented by the propensity of epithelial cells to die in suspension, or in the absence of the appropriate tissue survival Clearly, the fact that these processes trigger apoptosis creates selective pressure to mutate apoptotic programs during tumor development. Apoptosis in suspension is controlled by a number of other molecules, including the focal adhesion kinase and signal transduction pathways Some studies argue that p53 and Bcl-2 can also influence cell death in suspension 43and others observe enrichment for p53 mutations or Bcl-2 overexpression in metastases 44 Hence, loss of apoptosis can impact tumor initiation, progression and metastasis.
Mechanisms of apoptosis Although the primary focus of this review is on the biology of apoptosis in cancer, much is known about the biochemical action of many apoptotic players, and key components are being assembled into pathways. Activated caspase-8 initiates a protease cascade that cleaves cellular targets and results in apoptotic cell death Hence, disruption of FADD can prevent activation of caspase-8, thereby producing defects in receptor-mediated cell death This pathway is rarely the target of oncogenic mutations, but, if anything, it is enhanced during tumor development see below.
Growth factors, cytokines and DNA damage appear to signal cell death through the mitochondria, and this pathway is the target of many oncogenic mutations. These diverse signals affect the function of Bcl-2 family members which, in turn, can modulate the mitochondrial function though the permeability transition pore PTPa proposed channel evolved in mitochondria following necrotic or apoptotic signals.
The PTP is thought to be composed of clustered components of the mitochondrial membranes, including the voltage-dependent anion channel and adenine nucleotide translocator; and the opening of PTP results in the release of cytochrome c from mitochondria Consistent with this idea, the crystal structure of Bcl-xL is reminiscent of pore-forming proteins of some bacterial toxins Consequently, in order for cancer to develop and progress, apoptosis must be inhibited.
Cell death also plays major roles in cancer treatment, serving as the main effector function of many anti-cancer therapies. In this review, we discuss the role of apoptosis in the development and treatment of cancer.
Specifically, we focus upon the mitochondrial pathway of apoptosis—the most commonly deregulated form of cell death in cancer. In this process, mitochondrial outer membrane permeabilisation or MOMP represents the defining event that irrevocably commits a cell to die.
We provide an overview of how this pathway is regulated by BCL-2 family proteins and describe ways in which cancer cells can block it. Finally, we discuss exciting new approaches aimed at specifically inducing mitochondrial apoptosis in cancer cells, outlining their potential pitfalls, while highlighting their considerable therapeutic promise.
This altruistic cellular process plays varied and essential roles in keeping us healthy, not least in protecting us from cancer. Many oncogenic stresses, including uncontrolled proliferation or DNA damage, trigger apoptosis; consequently, by culling cells at risk of transformation, apoptosis effectively prevents cancer.
Apoptosis also suppresses tumourigenesis in various other ways. For example, matrix detachment of cells—a pre-requisite for metastatic disease—induces a form of apoptosis called anoikis. In short, for cancer to initiate and progress, apoptosis must be inhibited at multiple stages.
Cell death also plays key roles in the treatment of cancer. The best way to treat cancer is to kill it; indeed many anti-cancer therapies do this by inducing cell death through various mechanisms. Therefore, inhibition of cell death can act as a double-whammy that both promotes tumourigenesis and inhibits treatment responses.
Nevertheless, although inhibition of cell death promotes cancer, tumour cells themselves often remain sensitive to apoptosis. Indeed, cancer cells are often more sensitive to cell death than normal tissue. As we will discuss in more detail later, this paradox can be explained because of the inherent stresses that tumour cells face, effectively pushing them closer to the edge.
Mitochondria, apoptosis and cancer
Importantly, this can provide a therapeutic window to selectively trigger tumour death. In this mini-review, we will discuss the role of cell death in cancer development and treatment, specifically focusing upon the mitochondrial pathway of apoptosis.
Besides being the most commonly deregulated type of cell death in cancer, our understanding of mitochondrial apoptosis is now such that novel therapies have been developed to specifically engage mitochondrial apoptosis. Although we will restrict our discussion to mitochondrial apoptosis, it is important to note that other forms of programmed cell death, notably necroptosis also exist.
- Mitochondrial apoptosis: killing cancer using the enemy within