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[Cancer Research 63, 5118-5125, August 15, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Rottlerin Sensitizes Colon Carcinoma Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis via Uncoupling of the Mitochondria Independent of Protein Kinase C1

David M. Tillman, Kamel Izeradjene, Kinga Szekely Szucs, Leslie Douglas and Janet A. Houghton2

Division of Molecular Therapeutics, Department of Hematology-Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105

Signaling pathways involved in survival responses may attenuate the apoptotic response to the cytotoxic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in human colon carcinomas. In six lines examined, three were sensitive (GC3/c1, VRC5/c1, HCT116), HT29 demonstrated intermediate sensitivity, and RKO and HCT8 were resistant to TRAIL-induced apoptosis. Calphostin c [an inhibitor of classic and novel isoforms of protein kinase C (PKC)] sensitized five of six cell lines to TRAIL, whereas Go6976, (inhibitor of classic PKC isoforms), did not influence TRAIL sensitivity. Rottlerin, an inhibitor of novel isoforms of PKC, specifically PKC{delta}, sensitized five of six cell lines to TRAIL-induced apoptosis, suggesting that PKC{delta} may be involved in the mechanism of TRAIL resistance. Transfection of HCT116 with a proapoptotic cleaved fragment of PKC{delta} or an antiapoptotic full-length PKC{delta} did not influence the sensitivity of HCT116 to TRAIL. Furthermore, the incubation of HCT116 or RKO with phorbol myristate acetate for 16 h, which down-regulated the expression of novel PKC isoforms, also did not influence sensitivity to TRAIL either in the absence or presence of rottlerin. However, after 15-min incubation with rottlerin, mitochondrial membrane potential ({Delta}{psi}m) was dramatically reduced in RKO cells, and, in cells subsequently treated with TRAIL, rapid apoptosis was evident within 8 h. Calphostin c, but not Go6976, also caused a decrease in {Delta}{psi}m. In RKO, rottlerin induced the release of cytochrome c, HtrA2/Omi, Smac/DIABLO, and AIF from the mitochondria, potentiated in combination with TRAIL, with concomitant caspase activation and down-regulation of XIAP. In HT29, the release of proapoptotic factors was demonstrated only when rottlerin and TRAIL were combined, and Bcl-2 overexpression inhibited this release and the induction of apoptosis. TRAIL-induced apoptosis was not influenced by rottlerin or Bcl-2 overexpression in type I (GC3/c1) cells. Data suggest that rottlerin affects mitochondrial function independent of PKC{delta}, thereby sensitizing cells to TRAIL, and that mitochondria constitute an important target in overcoming inherent resistance to TRAIL in colon carcinomas.




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