Friday, May 22, 2015

The Role of Telomerase Activity in Urothelial Cancer

Telomerase is an enzyme whose activity within a cell leads to cell immortality due to repeated cell divisions.   The telomerase enzyme is highly active in embryonic cells and in stem cells where uninterrupted cell divisions are requisite for the role of these cells in the growth and development of the individual organism.    In addition, telomerase activity is a significant factor in cancer – its activity has been shown to be up-regulated in over 85% of cancers.  However, there is no detectable telomerase activity in most somatic – body – cells.  This lack of activity is due to the suppressed production of telomerase reverse transcriptase (TERT).  It has been suggested that mutations associated with TERT reactivation may be the, “most prevalent of all noncoding mutations in cancer.”

The question, of course, arises as to what is the cellular event that turns on telomerase activity in cancerous cells.  Due to exhaustive genetic analysis, there is evidence of point mutations in the TERT gene promoter in many cancer types including urothelial cancer (UC) – UC ranks five in the number of cancer cases reported in the Western world.  However, it remained unclear as to whether any of these mutations actually results in the reactivation of telomerase.

Dr. Sumit Borah from Howard Hughes Medical Institute at the University of Colorado BioFrontiers Institute in Boulder Colorado and collaborators from other institutions have done genetic studies on cell lines from 23 different UC patients.  They have clearly shown a correlation between these mutations and higher levels of TERT messenger – mRNA -, TERT protein and, most importantly, telomerase enzymatic activity.   Furthermore this group of investigators has established that elevated levels of TERT m-RNA expression is strongly associated with reduced survival in two independent UC patient studies.

These findings are highly significant; because they further elucidate the underlying genetic mechanisms that can transform a normal cell into a cancerous one. 

Thursday, May 14, 2015

How the Ebola Virus Gains Entry into its Target Cell

Many viruses that have been studied require a specific cell surface receptor in order to gain entry to their target cell(s).  To this date, no specific cell surface receptor has been identified for the Ebola virus.   The Ebola virus is responsible for a highly infectious disease referred to as hemorrhagic fever in humans.  However, important strides have been made in understanding the mechanism of Ebola virus infection.

Once the Ebola virus successfully binds specifically to its host cell, it is engulfed by a process known as micropinocytosis that encapsulates the virus in a cell organelle referred to as endosome – a membrane-bound vesicle.  While within this environment, the virus’ surface glycoproteins are cleaved through the action of a protease (an enzyme that degrades proteins).

The process by which the virus is ultimately released from the endosome into the intracellular environment remains to be completely characterized.  However Dr. Yasuteru Sakurai and his colleagues from the Texas Biomedical Research Institute in San Antonio Texas have elucidated an important step in this process.  Through exhaustive and painstaking studies they have shown that endosomal calcium channels – two-pore channels (TPCs) are necessary for the release of the Ebola virus from the endosome that holds it.

More importantly, from a therapeutic standpoint, the investigators used a number of research techniques to disrupt TPC function including gene knockout – where the gene responsible for the production of TPC protein is rendered dysfunctional  - and were able to effectively disrupt virus trafficking and, thereby, prevent infection.  Finally the use of Tetrandrine -  a calcium channel blocker possessing anti-inflammatory, immunologic and antiallergenic effects - inhibited infection of human macrophages; these cells have been shown to be the primary target of the Ebola virus in an in-vitro setting.

These are important findings for a number of reasons.  They demonstrate that TPC-related proteins play an essential role in the Ebola virus infection process.  In addition, their preliminary results using Tetrandrine illustrate how this information may be used to develop effective strategies against hemorrhagic fever.