Anticancer genes have a special ability to target and kill cancer cells without harming healthy ones. They do this through processes like programmed cell death, known as apoptosis, and other mechanisms like necrosis and autophagy. In the late 1990s, researchers discovered these genes while studying cancer cells. Sometimes, mutations or changes in these genes can occur, which might lead to cancer. These changes can include small alterations in the DNA sequence or larger rearrangements that affect the gene's function. When these anticancer genes are lost or altered, it can disrupt their ability to control cell growth, potentially leading to the development of cancer.
Anticancer genes as therapeutics
Cancer is a group of diseases where cells multiply uncontrollably. Normally, cells have a built-in process called apoptosis that triggers cell death to prevent excessive growth. However, when these processes are disrupted, cancer can develop. Studies show that cancer is one of the leading causes of death worldwide. Despite this, recent advancements in treatment have significantly increased survival rates for many patients.
The treatment for cancer varies depending on its type and how advanced it is. Chemotherapy is a common treatment that uses drugs to kill cancer cells. It works by damaging the DNA of cancer cells or stopping them from dividing. This process can also impact genes that control cell growth, affecting both cancer-causing and anticancer genes.
Summary of anticancer genes Anti-cancer geneFunctional p53 requiredBlocked by Bcl-2Caspases involvedActivated by phosphorylationEngaging cell death pathwaySubcellular localization in cancer cellsType of cell deathApoptinNoNoYesYesIntrinsicNucleusApoptosisBrevinin-2RUndeterminedYesNoUndeterminedIntrinsicCytoplasmAutophagyE4orf4NoNoNoYesIntrinsicNucleus, cytoplasmMitotic catastropheHAMLETNoNoYesNoIntrinsicNucleus, ER, mitochondriaApoptosis, autophagyMDA-7NoYesYesNoIntrinsicReceptor-binding, ERApoptosisNoxaNoYesYesUndeterminedIntrinsicMitochondriaApoptosisNS1NoNoNoYesIntrinsicCytoplasmApoptosisORCTL3UndeterminedUndeterminedYesUndeterminedIntrinsicPlasma membrane, ER, golgiApoptosisPAR-4NoNoYesYesExtrinsic, IntrinsicNucleus, ER, plasma membraneApoptosisTRAILNoYesYesNoExtrinsicReceptor-bindingApoptosis
Common anticancer gene examples
APOPTIN
History Apoptin was the first anticancer gene to be identified. It originates from the Chicken Anemia Virus (CAV), which has circular DNA. This virus belongs to the Gyrovirus family and is being researched for its potential in cancer treatment and diagnosis. The apoptin protein, also known as viral protein 3 (VP3), was first isolated from chickens and has been found to cause programmed cell death in human cancer cells.
Apoptin induces apoptosis, or cell death, in deformed or cancerous cells independently of a protein called p53, meaning it is active in cells deficient of p53, as well as those with mutated or wild-type p53 expression. In cancer cells, apoptin is mostly found in the nucleus and is activated, while in normal cells, it remains inactive in the cytoplasm. This difference allows apoptin to selectively target cancer cells.
Research has shown that apoptin can detect early changes that lead to cancer and can convert survival signals in cancer cells into signals for cell death. It interacts with various proteins, such as DEDAF, Nur77, Nmi, Hippi, and APC1. Studies using animal models and genetically modified mice have demonstrated that apoptin is a safe and effective anticancer agent, capable of significantly reducing tumor size. It holds promise for future cancer therapies as a treatment target and an early indicator of tumor-specific processes.
Action Apoptin is unique in its ability to attack deformed and cancerous cells while sparing healthy ones. It induces apoptosis through a pathway that involves mitochondria but does not rely on the p53 protein or death receptors typically involved in cell death. In healthy cells, apoptin stays in the cytoplasm, but in cancer cells, it moves to the nucleus after being activated by a process called phosphorylation. This movement is triggered by the enzyme CDK2 at a specific site on the protein.
For apoptin to function fully, it requires interactions with other molecules such as DNA, cyclinA-CDK2, and FADD. Current therapeutic agents using apoptin have shown effectiveness in treating types of cancer like Lewis lung carcinomas and osteosarcomas, with potential applications in liver cancer treatment.
Brevinin-2R
Brevinin 2R:
Skin from the frog Rana brevipoda porsa (now known as Pelophylax porosus) was used to isolate the unique non-hemolytic defensin known as brevinin-2R. Malignant cells such as T-cell leukemia Jurkat, B-cell lymphoma BJAB, colon cancers HT29/219, SW742, fibrosarcoma L929, breast cancer MCF-7, and A549 (lung carcinoma) exhibit preferential cytotoxicity towards it in comparison to primary cells such T cells, human lung fibroblasts, and peripheral blood mononuclear cells (PBMC). Jurkat, MCF-7, and L929 overexpressing cells as well as MCF-7 cells overexpressing a dominant-negative mutant of a pro-apoptotic BNIP3 (TM-BNIP3) were largely resistant to Brevinin-2R treatment.
Action These 25 amino acid peptides, in contrast to the majority of peptides within the Brevinine family, have low hemolytic action. Not only does the peptide have a reduced hemolytic action, it also is semi-selective towards cancer cells and leaves non-cancerous cells largely unharmed. This peptide works to prevent the progression of cancer by arresting the cell cycle at the G2/M phase, resulting in an induction of apoptosis.
This defensin traditionally works as a part of the innate immune system, working as an antimicrobial defense. However, this peptide is currently being studied as an anticancer peptide. Brevinin-2R works to trigger cell death by reducing the mitochondrial membrane potential resulting in lower cellular ATP levels while simultaneously increasing the concentration of reactive oxygen species. Currently and somewhat unrelated, Brevinin-2R is being considered for diabetic treatments. In treating type II diabetes, or diabetes mellitus, Brevinins have been shown to promote insulin release. Finally, these peptides even have the capability to increase the rate of tissue regeneration, as seen with the frog in which Brevinin-2R was isolated from.
E4orf4
History Early region 4 open-reading-frame 4 (E4orf4) is an adenovirus protein of 14kDa which regulates growth in all stages of the adenovirus (Ad) infection. E4orf4 partners mainly with protein phosphatase 2A (PP2A) and Src kinases to induce cell death. Modeling of this protein reveals that it is likely made up of 3 α-helices with N- and C-terminal loops. It has a small stretch of amino acids in positions 66–75, which are highly basic, and likely are a place of nuclear and nucleolar targeting, as well as a place for Src kinases to bind.
Action E4orf4 is an important regulator of adenoviruses. Additionally, outside of the context of the virus, it causes programmed cell death both in the context of a healthy cellular environment, and cancer. E4orf4 is a key regulator of Ad by down-regulating both viral and cellular genes, which plays an important role in regulating the proliferation of the virus. In turn, the down-regulation also impacts the alternative splicing of the viral RNA and protein translation. In the absence of a viral infection, E4orf4 induces apoptosis in a p53 and caspase-independent manner; however, there is still communication between this pathway and the caspase-dependent apoptosis pathway. In the context of cancer, E4orf4 is even more efficient at inducing cell death than in healthy cells, which could be an important finding for potential cancer therapies. It has been discovered that the mechanisms behind the function of E4orf4 are closely associated with several other proteins including the B55 subunit of PP2A. E4orf4 binds to PP2A to reduce the phosphorylation of the DNA damage response (DDR) proteins. Consequently, this reduces the function of DDR and limits DNA repair. Many cancer cells have defects in the DDR pathways and targeting these cells with E4orf4 can potentially destroy the remaining DDR pathways, resulting in cancer cell death.
The main mechanism behind the specificity of cancer cell targeting by E4orf4 is unknown but there are multiple hypotheses that scientists are considering: 1) The activation of the oncogenic state causes dormant apoptotic signals to be initiated and cause cell death to be more easily achieved by different signals. 2) There has been some indication that cancer cells become addicted to oncogenic pathways. E4orf4 may inhibit these pathways, causing cell death in cancer cells, but not normal cells. 3) E4orf4 may use oncogenes that have been activated in cancer cells, including Src, to cause cell death. 4) Cancer cells have disrupted cell cycle checkpoints and E4orf4 can take advantage of this by disrupting checkpoints in mitosis. 5) A Drosophila model demonstrated that E4orf4 can inhibit classical apoptosis in healthy tissues. It has been considered that this function of E4orf4 is lost in cancer cells causing a more effective killing of cells. 6) E4orf4 has been shown to cause structural changes in mitochondria, which could impact metabolic reprogramming and may affect cancer and healthy cells differently.
HAMLET
History HAMLET is known as an anticancer protein complex found in breast milk. One of the two molecules of this complex is multimeric alpha lactalbumin (MAL), which was first discovered during a study in 1995 that investigated how breast milk affects bacteria transformed with lung cancer. This study found that transformed cells were selected for apoptosis at a much higher rate than the untransformed, healthy cells. A later study in 2000, ascertained that oleic acid, a C18:1 fatty acid, is a cofactor that binds to MAL forming HAMLET. This complex, in a partially unfolded state, then displays apoptotic activity in cancer cells.
Action Apoptosis, or programmed cell death, can occur through activation of three different pathways, intrinsic, extrinsic, or tumor necrosis factor. HAMLET proceeds by both a multifaceted intrinsic pathway and the caspase cascade, a subsection of the TNF pathway, through targeting many different cell components. First, after uptake by the cell, HAMLET proceeds to the mitochondria and depolarize the membranes at cytochrome c. Consequently, mitochondria-dependent apoptosis factors are released as well as the caspase cascade is activated. Second, proteasomes are targeted by HAMLET through a mechanism that is less understood. Research does suggest that HAMLET directly binds to the proteasome leading to its inhibition. Third, HAMLET has been found to target the nucleus, specifically histones. HAMLET irreversibly binds to histones leading to the inactivation of transcription and chromatin condensation, which inevitably causes apoptosis. Lastly, studies show that cells treated by HAMLET exhibit behaviors common to macroautophagy. This includes the presence of cytoplasmic vacuoles, double-membrane vesicles, and a dose-dependent decrease in ATP levels.
MDA-7
History