This essay explores the role and importance of the telomerase enzyme in cancer biology and cancer research with an in-depth discussion on the background, discovery, structure, and function of both telomerase and the telomere. Telomerase is a ribonucleoprotein that is responsible for the elongation of chromosomes by accumulating the TTAGGG sequences at the terminal end of these chromosomes. Telomerase is present in the germ cells of adults, fetal tissues and cancer cells. Unregulated telomerase activity has long been implicated in cancer. Telomerase is normally regulated by numerous pathways and components including mTORpathway. The importance of telomerase and its activity in cancerous cells has been elaborated in detail with stress on the inhibition studies of the telomerase activity for the development of drugs related to cancer. Telomerase is associated with the mTOR (mammalian Target of Rapamycin) pathwayas well as with estrogen receptors, as the transcription of the hTERT protein is dependent upon and regulated by estrogen, among other steroid hormones. The mTOR pathway plays an important role in the regulation of the post-translational modification of the hTERT protein and its activity. Breast cancer is a prevalent type of cancer among women across the world. Isoprenoids have long been known to play a role as anti-cancer agents in prostate cancer cells and the isoprenoid, perillyl alcohol, has been shown to inhibitprostate and estrogen receptor positive breast cancer cells. In prostate cancer cells, perillyl alcohol was shown to act on telomerase via the mTOR pathway but the mechanism is not elucidated in the estrogen receptor positive breast cancer cells. In this essay, I hypothesize that perillyl alcohol acts as a potential inhibitor of telomerase in the estrogen receptor positive breast cancer cells, which if verified would help in future drug development related to breast cancer.
hTR: human Telomerase RNA
hTERT: human Telomerase Reverse Transcriptase
mTOR: mammalian Target of Rapamycin
POH: Perillyl Alcohol
OverviewWorld-wideprevalence of breast cancer is very high with almost 400,000 recorded deaths every year and about one million new diagnoses in the same time frame(Porika et al., 2011). The development of cancer has long been linked to the telomere and its associated enzymetelomerase (de Lange, 2004). Thepresence of dysfunctional telomeres leads to chromosomal instability in cancers (Porika et al., 2011). As shown below, telomeres and telomerase are also being used to further the scope of available treatment options.
Telomerase enzyme expression is regulated by a number of factors including hormones, such as estrogen. Estrogen is a positive regulator of the expression of the hTERT gene, which encodes the reverse transcriptase component of telomerase (Murillo-Ortiz et al.,2006). Breast cancer cells can be either estrogen-receptor-positive (ER-(+)) and therefore responsive to estrogen or they can be ER-negative. Hence, cancer cells that are ER-(+) can be targeted specifically to study the inhibition of telomerase activity.
Telomerase activity in cancer cells has been inhibitedusing a number of compounds that have shown potential for their clinical application (Sundin et al., 2012). The mTOR (mammalian Target of Rapamycin) pathway is one of the most studied pathways in relation to oncogenesisand one of its roles is to regulate telomerase activity. Therefore, an additional avenue to increase treatment options for cancer might be to develop compounds that inhibit telomerase activity targeting the mTOR pathway. Combining the two avenues of the inhibition of telomerase activity directly and the regulation of the mTOR pathway opened a new gateway in cancer research.
mTOR is a serine-threonine protein kinase that controlscell survival, proliferation and growth. Its normal function is to sense the nutritional and energy status of theintracellular environment; in cancer, mTOR signaling is frequently upregulated (Azab, 2013). Among the different compounds that have shown promise as a cancer therapeutics isthe isoprenoid, perillyl alcohol (POH); isoprenoids are known for their suppressing ability of carcinogenic mechanisms in vitro and in vivo (Muller, 1962).Perillyl Alcoholhas proven to be effective in the inhibition of telomerase activity in pancreatic cancer (Wiseman, Werner & Crowell, 2007).Perillyl Alcoholacts on the translation of hTERT proteins via the downward modulation of mTOR signaling (Sundin et al. 2012).
HypothesisPerillyl Alcoholis successful as an oral systemic cancer treatment in animals (Sundin et al., 2012). It is also successful on both human prostate (Sundin et al., 2012) and ER-(+) breast cancer cells(Yuri et al.,2004), although the mechanism of inhibition by POH in prostate cancer cells is known to be through its impact on telomerase activity. Nothing is known about its effects on telomerase activity in ER-(+) breast cancer cells. The hypothesis of this essay is that POH inhibits telomerase activity in the ER-(+) breast cancer cells.
Chapter 1: TelomeresBackgroundTelomeres arenucleoprotein structures present at the ends of the chromosomes and have important roles in protecting the genetic information and facilitating maintenance of the process of cell division (Watson and Crick, 1953). They play a number of roles that inturn maintain the genome stability and its function. The roles include protecting the chromosomes from inappropriate end-to-end fusions, thus maintaining the structural integrity of the chromosomes, as well as preventing any sort of inapt recombination events (Greider and Blackburn, 1985).The telomeres maintain the stability of the chromosomes by distingushing their ends from DNA double stranded breaks and retaining the chromosome length (Greider and Blackburn, 1985). Primarily, telomeres play essential roles in the maintenance ofchromosome length, aging, recombination, and cancer development.
Cell division is a universal process necessary for all living creatures through which the chromosomes within the nucleus undergo duplication and equal distribution of the genetic information from the mother cell into two daughter cells.Consequently, cells multiply and form the tissues and organs during the development of multicellular organisms. Due to the vital nature of cell division, an orderly progression occurs in a regulated manner proceeding through the cell cycle(McClintock, 1941). Left to itself, during every round of DNA replication, chromosome shortening will occur due to an event known as the end-replication problem (Olovnikov, 1973). Telomeres and telomerase have important roles in preventing this event, which will be discussed below.
Replication of DNA and the end-replication problem
In 1953, Watson and Crick proposed that DNA replication is semi-conservative (Watson and Crick, 1953); this hypothesis was later supported by the Meselson-Stahl experiment (Meselsonand Stahl, 1958). Each strand of DNA in the chromosome acts as a template for replication, which begins in an origin of replication and continues in a 5' to 3' direction on each DNA strand resulting in the formation of a replication fork (Bell, 2006; see Figure 1).
Figure 1: A DNA Replication Fork: Leading strand: DNAs daughter strand and it runs in the 5'-3' direction towards the replication fork. DNA polymerase replicates this strand continuously. Lagging Strand: daughter strand of DNA that runs in the 5' - 3' direction towards the replication fork. Its replication is discontinuous and this leads to the formation of diminutive Okazaki fragmentswhich are connected together later. Okazaki Fragments:Yellow arrows represent short DNA fragmentsthat are synthesized during the replication of the DNA on the lagging strand. (Figure adapted fromBell, 2006)
DNA replication involves numerous proteins and enzymes that causes the unwinding of the DNA double helix. This occurs in response to the synthesis of a short RNA strand resulting from the use of the helicase enzyme. The proteins function to hold in position the DNA strands that have yet to be unwound. Every DNA strand sets a base for the synthesis of its complementary strand. In addition, the appropriate nucleotides are bound together by the DNA polymerase III. Although the process is much more complicated than presented here, the basic process of DNA replication begins with theformation of an RNAprimer complementary to the origin of replication DNA sequences. The process of DNA replication has to occur before cell division to ensure that the new cells have sufficient amount of DNA material (Yu et al, 1990). The RNA primer is synthesized by primase, anRNA polymerase and DNA helicase unwinds the DNA into two separate strands by the denaturation of the hydrogen bonds between the nucleotide bases using the energy derived from ATP hydrolysis in the nucleic acid phosphodiester backbone (Yu et al, 1990); the single-stranded DNA within the replication bubble is maintained with the help of single-strand binding proteins.
Both DNA strands are replicated in the 5' to 3' direction, although the process is different. The synthesis of one of the daughter strands, called the leading strand, occurs continuously towards the replication fork(See Figure 1). DNA polymerase a synthesizes daughter strands by adding matching nucleotides to the existing template strand with the formation of phosphodiester bonds between the nucleotides (Buckingham, 2012). The nucleotides exist as nucleoside triphosphates and the two distal phosphates are released. A pyrophosphate and this enzymatic hydrolysis of the high energy phosphate bond using DNA polymerase a causes DNA polymerization to occur (Yu et al, 1990). .
The synthesis of the other daughter strand, called the lagging strand, occurs in segments, known as Okazaki fragments, going away from the replication fork (See Figure 1). For eachOkazaki fragment, aRNA primer is present and must be removed and replaced with DNA usingDNA polymerase and Flap endonucleases. DNA Polymerase generates the flap structures during the extension of the Okazaki fragments when it encounters the previous primer. Flapendonucleaseremoves or cleaves the short flap-like structures that are subsequently formed. Once Okazaki fragments have been formed, the RNA primers that take part in the synthesis are replaced with DNA and the various segments are bound together by DNA ligase. This proc...
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