Table of Contents

Viewpoints

• • Harald Wajant

  Targeting the FLICE Inhibitory Protein (FLIP) in Cancer Therapy

  Mol Interv May 2003 3:124-127; doi:10.1124/mi.3.3.124
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  In some cases, treatment of ovarian cancer cells with tumor necrosis factor-α can induce an apoptotic signal leading to the death of these cells; however, many ovarian malignancies are resistant to the effects of TNF-α. A new publication describes how these ovarian tumors may evade death receptor-mediated apoptosis. Apparently, the extracellular signals transduced by death receptors (e.g., TNF receptors) are extinguished before the cascade of caspases, which proteolytically cleave other proteins, can be activated. Overexpression of FLIP, a protein that blocks the caspase activity of FLICE, mediates the observed resistance. Thus, FLIP, which normally prevents inappropriate apoptosis, may become a tumor progression factor. Strategies to overcome this FLIP-mediated blockade of programmed cell death in tumors might become useful for positive prognoses.

• • Stéphanie Dutertre and
  • Claude Prigent

  Aurora-A Overexpression Leads to Override of the Microtubule-Kinetochore Attachment Checkpoint

  Mol Interv May 2003 3:127-130; doi:10.1124/mi.3.3.127
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  The amplification of AURORA-A is frequently observed in specific epithelial cell malignancies. The overexpression of aurora-A, a Ser-Thr kinase known to localize to centrosomes during mitosis, appears to imbue cancerous cells with resistance to spindle-checkpoint-targeting drugs such as paclitaxel (Taxol). Indeed, a recent publication by Anand et al. indicates that overexpression of AURORA-A may interefere with spindle-microtubule attachment and disrupt the regulation of the spindle checkpoint by allowing cells with abnormal chromosomal separation to enter anaphase. Thus, the design of new drugs that specifically target aurora-A rather than other checkpoint proteins might alleviate the resistance to Taxol-like clinical therapeutics observed in some tumors.

• • Sandro Yong,
  • Xiaoli Tian,
  • and Qing Wang

  LQT4 Gene: The “Missing” Ankyrin

  Mol Interv May 2003 3:131-136; doi:10.1124/mi.3.3.131
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  Mutations in ion channels have been implicated in the formation of long QT syndrome (LQTS). However, Mohler et al. have recently uncovered a role for ankyrin-B, a non-ion channel protein, in type IV LQTS. Calcium signalling is altered, and the functions of several channels and pumps that normally interact with wild-type ankyrin-B are impaired in the presence of mutant ankyrin-B. The authors suggest that by disrupting the functions of these channels, a new mechanism has been uncovered that can lead to cardiac myopathy.