One of the most Leading Cause of Death Globally is Cancer
One of the most leading cause of death globally is cancer and it is responsible for 8.8 million deaths in 2017. It is expected that there would be 70% rise in the number of new cases of cancer in the next two decades. Cancer causes nearly 1 in 6 deaths globally. Cancer is a complex disease involving changes at genetic & epigenetic levels and is characterized by uncontrolled cell growth. It can be of two types- Malignant and Benign. A benign tumor is not a cancerous. A non cancerous tumor is unable to spread throughout the body. The word malignant is Latin which means “badly born.” This type of tumor is characterized by uncontrolled cell division, and has the ability to metastasize (spread) to various parts of the body and it invades the surrounding tissue.
The Process of Metastatis: In this complex process, cells are detached from a primary and vascularized tumor, then it penetrates the surrounding tissue, and enters the nearby blood vessels (intravasation) and eventually circulates in the vascular system. Some of these cells adheres to blood vessel walls and have the ability to extravasate and migrate into the local tissue, thereby forms a secondary tumor.
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Cancer Hallmarks: A review article authored by Douglas Hanahan “THE HALLMARKS OF CANCER” published in the Cell in 2000 categorized the cancer on the basis of hallmarks. In total, six hall marks were reported in the paper and later on new markers were also added to the list making it ten. The main characteristics includes the self sufficiency of cancerous cell in initiating growth via growth signals (such cells are generally insensitive to the antigrowth signals), capability to evade apoptosis, have effective replicative potential, sustained angiogenesis is one remarkable feature, invading new tissues and metastasis, instability in genome and prone to mutation, inflammation in the affected tissue, reprogramming of energy metabolism and furthermore (Hanahan D & Weinberg RA 2000).
Success of the cancer therapy greatly relies on the finding of specific and effective targets which are responsible for the abnormal cell division and proliferations. In-silico and in-vivo research activities of last few decades able to find out numerous target sites. However, despite the overwhelming findings of cancer targets non-specificity and inaccuracy of treatment results poor survival rates.
Survivin is a member of inhibitor of apoptosis proteins (IAP) family and is anti-apoptotic in nature. Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) encodes survivin, so it is also commonly called BIRC5. Compared with other IAPs that contain multiple domains, survivin is structurally unique as it contains only one single BIR domain. It is the smallest in the IAP family, has a molecule weight of 16.5 kDa, and contains 142 amino acid residues. Unlike other IAPs that are expressed in both cancerous and normal cells, survivin is expressed only in majority of the neoplasms but not in most normal differentiated tissues. Survivin contributes to tumor formation and maintenance because of its functional properties (mitosis regulation, cell proliferation, supporting angiogenesis, metastasis and chemo-resistance of tumor cells). Therefore, it has become a lead target for both as a tumour diagnostic, prognostic and as well as for anti-cancer therapies. Survivin overexpression inhibits both intrinsic and extrinsic pathways of apoptosis by inhibiting the activity of caspase-9 as well as affects the cell cycle. This ultimately causes inhibition of cancer cell apoptosis and thereby promotes cell proliferation. Moreover, expression of survivin in tumors also responsible for generation of drug resistance. Therefore, development of potential inhibitors against survivin would be considered as an ideal target for anticancer treatment.
A single gene of survivin gives four spliced transcripts alternatively-
- Survivin-Delta-Ex-3: In it exon 3 is removed. This results in a frame shift which leads to the generation of a unique carboxyl terminus with has a new function that may includes a localized nuclear signal. A localized mitochondrial signal is also there.
- Survivin-3B: It consists an inserted exon 3 alternatively.
- Survivin-2B: It consists an inserted exon 2 alternatively.
- Survivin: It consists of three-intron–four-exon structure.
A feature which is common in IAP family proteins is that they have at least one BIR (baculoviral IAP repeat) domain consisting of an conserved zinc-coordinating His/Cys motif which is present at the N-terminal half of the protein.
Survivin is the smallest member of the IAP family and its molecular weight is 16.5 kDa . As survivin has only one BIR domain so it is different from other IAP family proteins. The human survivin also has an C-terminal helix of 42 amino acids which is elongated. X-ray crystallography shows that two human survivin molecules comes together to form a dimer which is bowtie in shape by a hydrophobic interface. This interface consists of a 6-10 N-terminal residues just before the BIR domain region and a 10 residue region connects the BIR domain to the C-terminal helix.
Survivin expression in different cancer cells:- Survivin is expressed during development of foetus and in most of the cancer cell types, but it is rarely found in non-malignant normal adult cells. Tamm et al. showed that survivin was expressed in 60 different human cancer cell lines used in the National Cancer Institute’s cancer during screening of drugs. The highest level of expression was in lung and breast cancer lines and the lowest level of expression was in renal cancers. By finding out the relative level of expression of survivin in different cancer cells, therapies related to survivin can be done depending upon its level of expression .
Survivin- an oncogene:- Survivin is considered as an oncogene because of it is overexpressed in most of the tumour cells. This makes them resistant to apoptotic stimuli and chemo-therapies, thus enabling them to survive for long.
In stability of genome:- In most of the human cancer cell, there are gains or losses of chromosomes, due to CIN (chromosomal instability). One of the cause of chromosomal instability is the deactivation of genes that controls segregation of the sister chromatids in mitosis properly. In order to have a better understanding of survivin’s role in regulation of mitosis, researchers have looked into the domain of genomic instability. It is seen that in the beginning of mitosis, survivin gets associated with the microtubules of the mitotic spindle .
Through literature it is known that knocking survivin out of the cancer cells disturbs the formation of microtubule which causes apoptoisis massively or polyploidy. It is also seen that cells devoid of survivin exits mitotic cycle without chromosome alignment properly and then forms a single tetraploid nuclei. Survivin plays a major role in the progression of mitosis and in arresting mitosis. This is strange, as survivin is upregulated to a high level in most of the tumour cells (that usually consists of instabilities in chromosome), and its role is to promote regulation of mitosis properly.
It is the phenomena of programmed cell death, that includes complicated pathways of cell signalling and a series of molecular events. This is required for proper development of embryo and growth of foetus where destruction and reconstruction of structures of cells are involved. In adult organisms, apoptosis is necessary to maintain differentiated tissue by maintaining the balance between proliferation and cell death. It is known that when the death pathway is activated the intracellular proteases called as caspases degrade the cellular contents of the cell by proteolysis.
Extrinsic Pathway: This pathway is intiated by the extrinsic ligands that binds to the death receptors on the cell surface. An example is the binding of TNF-alpha (tumour necrosis alpha) to its receptor. An example of a TNF receptor is Fas (CD95). It allows activator caspases like caspase-8 on binding TNF at the surface of cell. Upon activation of the initiator caspases, a downstream series of events are initiated that causes the induction of effector caspases which has role during apoptosis.
Intrinsic Pathway: Intracelluar or environmental stimuli initiates this pathway. It detects the improper mitochondrial functioning in the cell and thus, activates pathways of cell signalling to commit suicide. The permeability of the mitochondrial membrane increases and some specific proteins are released in the cytoplasm that activates the initiator caspases. These proteins which are released is cytochrome c. Cytochrome c binds to Apaf-1 in the cytosol and this activates initiator caspase-9. Upon activation of the initiator caspases, a downstream series of events are initiated that causes the induction of effector caspases that functions during apoptosis.
IAPs like survivin, inhibit apoptosis by binding to and inhibiting caspase function. IAPs have a regulatory role in cell division. Yeast cells devoid of certain IAP genes do not show problems of cell death, but they show mitotic defects characterized by improper segregation of chromosome or cytokinesis failure. Changing the expression of particular IAPs, increases induction of cell death spontaneously or increment in sensitivity to death stimuli.
Survivin is absent in most normal cells and highly expressed in cancer cells, thereby its a good target for cancer therapy. Small interfering RNA (siRNA) are synthetic antisense oligonucleotides to the mRNA of the gene of interest that has role in silencing the expression of a specified gene by its complementary binding. siRNAs. A problem arises when expression siRNA in a cell cannot be controlled, thereby causing toxic side-effects. In practical treatment of cancer, it is needed either to control the expression of siRNA or to deliver siRNA into cancer cells specifically. It is known that survivin is absent in normal cells and is over-expressed in cancer cells absent. This shows that the survivin promoter is active only in cancer cells. Thus, the exploitation of this difference between cancer cells and normal cells will allow appropriate therapy directed only at the cancerous cells in a patient. To demonstrate, Trang et al. created a cancer-specific vector expressing siRNA for green fluorescent protein (GFP) under the human survivin promoter. MCF7 breast cancer cells were cotransfected with this vector and a GFP-expressing vector as well. It was founded that MCF7 cells transfected with the siRNA vector for GFP under the survivin promoter showed a significant reduction in GFP expression then the cells transfected with the siRNA vector under a cancer non-specific promoter. The normal non-cancerous cells transfected in the same way showed no significant reduction in GFP expression. Thus it is implied that, in normal cells, survivin promoter is not active, and the siRNA will not be expressed under an inactive survivin promoter.
Till date very less number of inhibitors of survivin have been developed, and most of these inhibitors reduces the level of survivin by interacting with other biomolecules instead of intereacting directly with survivin protein. Despite of such challenges, developing selective and potent small-molecule inhibitors of survivin will be important to understand the biology of survivin and to develop more potential and more effective anticancer agents. YM155, a small-molecule compound, was identified to inhibit expression of survivin. But its several phase II trials showed very less efficacy on human cancers. LY2181308, an antisense oligonucleotide, known to inhibit expression of survivin was tested in phase I trial as a single agent for solid tumors and then combined with docetaxel in phase II trial for castration-resistant prostate cancers. None of these two trials showed any success. Thus, it is needed to discover new inhibitors of surviving that binds to surviving directly. Presently, limited numbers of survivin inhibitors (15 approx.) are reported. Among them only YM155 and Termeprocol considered being best had showed limited efficacy on human cancers in clinical trials. The probable reason behind failure in clinical trials is that these inhibitors target survivin indirectly. In our proposed study, survivin will be targeted directly via small molecule inhibitors.”