Wednesday, 25 April 2012

Telomerase: A Cancer Therapeutic Target

Although Elizabeth Blackburn had identified telomerase in 1980, it took 29 years for her work to be truly recognised. In 2009, Blackburn and her esteemed colleagues were awarded the Nobel Prize in Physiology or Medicine based on the successful ‘discovery of how chromosomes are protected by telomeres and the enzyme telomerase’ (Nobelprize.org, 2012).
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Figure 1: Structural form of enzyme Telomerase

As a result of this initial discovery, many scientific studies and research projects have aimed to further understand telomerase and the way in which it is related to degenerative diseases, aging and cancer (Reece, 2011). One such study was conducted by Jian Hu from the Dana-Farber Cancer Institute, Boston, USA. Titled ‘Antitelomerase Therapy Provokes ALT and Mitochondrial Adaptive Mechanisms in Cancer’, the study looked at modeling telomerase reactivation through the use of an inducible telomerase reverse transcriptase allele (Hu, 2012).

The starting point for a mutation has been found to be related to a problem which can arise during cell division if the subject (mouse) has levels of the enzyme which are low or nonexistent. When this factor is married with conventional DNA polymerases exhibiting an end-replication problem a normal or premalignant cell can lose the essential telomere sequences and uncapping can occur (Hu, 2012). This leads to the activation of cellular checkpoints not unlike those caused by DNA double-stranded breaks and ultimately results in telomere dysfunction (Hu, 2012). Flow on effects of dysfunction can be seen with records of induced p53 (tumor suppressor protein), cellular senescence and apoptosis (Children’s Medical Research Institute, 2006). Mutational inactivation of the p53 protein allows for cell cycling to continue and provides a procarcinogenic mutator mechanism for cells with telomere dysfunction via translocations, amplification and deletions (Hu, 2012). However, continual dysfunction and uncontrolled chromosomal instability can restrict full malignant progression.

As a result, clinically derived inhibitors with oligonucleotide changes enable maintenance of telomeres through homologous recombination. The alternative lengthening of telomeres (ALT) mechanism is one such inhibitor. By engineering an allele, TERT (a reverse transcriptase catalytic subunit) which can be inserted into the genome, and using mice mutant for Atm, the development of high penetrance and T cell lymphomas was able to be modeled. Results showed that mice from either the parental or first generation with the allele 4-Hydroxytamoxifen (4-OHT)-inducible Telomerase Reverse Transcriptase-Estrogen Receptor (TERTER) developed T cell lymphomas at synonymous penetrance and latencies. In comparison, the third and fourth generation mice presented lymphomas with lower penetrance and longer latency (Hu, 2012), refer to Figure 2.
 Figure 2: Kaplan-Meier curves of T cell thymic lymphoma-free
survival for mice treated with 4-OHT or vehicle.

Several key genes including those that were regulated from a master regulator possessed deviant expression in relation to oxidative and mitochondria pathways. The PGC-1β, believed to control mitochondrial oxidative energy metabolism by activating specific target transcription factors including estrogen-related receptors (Sonoda, 2007), was found to be a major driver of the adaptive response to telomere dysfunction (Hu, 2012), refer to Figure 3.

 Figure 3: RT-qPCR validation of oxidative defense
genes upregulated in ALT+ lymphomas.


The pressure for a cell to maintain mitochondrial function is directly relatable to the ROS (reactive oxygen species) levels and may be of great importance to telomeres due to ROS destroying telomeric G-rich sequences. Thus confirming the PGC link (refer to Figure 4) between mitochondria, telomeres and carcinogenic cells (Hu, 2012).




Figure 4: Model of regulation of apoptosis, senescence and mitochondrial
function in telomerase+, ALT+ and telomere dysfunctional cells.

Furthermore, rendering genetic modelling crucial in the desire to understand tumor cell response, and quite possibly providing the answer to curing cancer.
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References
1.  Reece, J., Meyers, N., Urry, L., Cain, M., Wasserman, S., Minorsky, P., Jackson, R & Cooke, B, (ed.) 2011, Campbell Biology, pp. 323-324, Pearson Education, Inc., Australia.

2.    Children’s Medical Research Institute, 2006, p53 Tumor Suppressor Protein, viewed
      12 April 2012, <http://www.cmri.org.au/p53-Tumour-Suppressor-Protein/default.aspx>
3.    Hu, J., Hwang, S., Liesa, M., Gan, B., Sahin, E., Jaskelioff, M., Ding, Z., Ying, H., Boutin, A., Zhang, H., Johnson, S., Ivanova, E., Kost-Alimova, M., Protopopov, A., Wang, Y., Shirihai, O., Chin, L & DePinho, R, 2012, ‘Antitelomerase Therapy Provokes ALT and Mitochondrial Adaptive Mechanisms in Cancer’, Cell, vol. 148, no. 4, pp. 651-663, viewed 30 March 2012, <http://www.sciencedirect.com.ezproxy.library.uq.edu.au/science/article/pii/S0092867412000268>
4.    Sonoda, J., Mehl, I.R., Chong, L.W., Nofsinger, R.R. & Evans, R.M., 2007, ‘PGC-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis’, PubMed, viewed 30 March 2012, <http://www.ncbi.nlm.nih.gov/pubmed/17360356>
 
5.    Nobelprize.org, 2012, The Nobel Prize in Physiology or Medicine 2009, Nobel Media, viewed 2 April 2012, <http://www.nobelprize.org/nobel_prizes/medicine/laureates/2009>

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