Klin Padiatr 2004; 216 - 43
DOI: 10.1055/s-2004-828588

Down-regulation of PKCη or Bcl-xL, but not Bcl-2, potentiates the cytotoxic effects of TRAIL in prostate cancer cells

A Sagrauske 1, J Sonnemann 1, C Müller 2, JF Beck 2
  • 1Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Greifswald, Germany
  • 2Pädiatrische Onkologie und Hämatologie, Ernst-Moritz-Arndt-Universität, Greifswald, Germany

TRAIL is a promising candidate for the treatment of cancer. However, some tumours display resistance to TRAIL, prompting us to explore whether the apoptotic responsiveness of cancer cells to TRAIL could be enhanced by targeting the novel PKC isoform η, Bcl-2 and Bcl-xL. Transfection of PC-3 cells with second-generation antisense oligonucleotides caused a significant knockdown of the corresponding mRNAs and proteins as revealed by real-time RT-PCR and Western blot analyses. Knockdown of either PKCη or Bcl-xL, but not Bcl-2, and administration of TRAIL significantly synergised in inducing apoptosis (as evidenced by Alamar Blue assay, cell cycle analysis, determination of Δψm, caspase-3 and -9 activities). We conclude that Bcl-2 and Bcl-xL have distinct functions, and that PKCη and Bcl-xL represent targets to exploit the therapeutic potential of TRAIL. The significance of these findings will be explored in studies on childhood cancers.

This work was supported by the Wilhelm Sander-Stiftung, Neustadt/Donau and by the Deutsche Krebshilfe.