Elimination of Hepatic Metastases of Colon Cancer Cells via p53-Independent Cross-Talk between Irinotecan and Apo2 Ligand/TRAIL

Abstract

The majority of colorectal cancers have lost/inactivated the p53 tumor suppressor gene. Using isogenic human colon cancer cells that differ only in their p53 status, we demonstrate that loss of p53 renders tumor cells relatively resistant to the topoisomerase I inhibitor, irinotecan. Whereas irinotecan-induced up-regulation of the proapoptotic proteins PUMA and Noxa requires p53, we find that irinotecan inhibits Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 and 5 (STAT3/5) signaling in both p53-proficient and p53-deficient tumor cells. We show that irinotecan inhibits JAK2-STAT3/5-dependent expression of survival proteins (Bcl-x L and XIAP) and cooperates with Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) to facilitate p53-independent apoptosis of colon cancer cells. Whereas xenografts of p53-deficient colon cancer cells are relatively resistant to irinotecan compared with their p53-proficient counterparts, combined treatment with irinotecan and Apo2L/TRAIL eliminates hepatic metastases of both p53-proficient and p53-deficient cancer cells in vivo and significantly improves the survival of animals relative to treatment with either agent alone. Although the synergy between chemotherapy and Apo2L/TRAIL has been ascribed to p53, our data demonstrate that irinotecan enhances Apo2L/TRAILinduced apoptosis of tumor cells via a distinct p53-independent mechanism involving inhibition of JAK2-STAT3/5 signaling. These findings identify a novel p53-independent channel of cross-talk between topoisomerase I inhibitors and Apo2L/TRAIL and suggest that the addition of Apo2L/TRAIL can improve the therapeutic index of irinotecan against both p53-proficient and p53-deficient colorectal cancers, including those that have metastasized to the liver.

Oncogenic KRAS sensitises colorectal tumour cells to chemotherapy by p53-dependent induction of Noxa

“…Therefore, the loss of Noxa function does not seem to be required during colorectal tumour development. Indeed, the Noxa-dependent apoptosis pathway is intact in colorectal tumour cells (Ravi et al, 2004;Okumura et al, 2008). Furthermore, Noxa has been identified as a tumour-specific inducer of breast carcinoma cell death that spares non-transformed mammary cells (Suzuki et al, 2009).…”

Effects of prodigiosin family compounds fromPseudoalteromonassp. 1020R on the activities of protein phosphatases and protein kinases

“…This may be explained by the hydrophobic nature of these compounds, which enables them to penetrate through the lipophilic membrane bilayer. However, prodigiosininduced apoptosis via the death receptor signaling extrinsic pathway is also important, as it was reported not to involve p53 signaling 7 . In fact, as supported by our results, prodigiosins are known to cause apoptosis both dependently 8 and independently [8][9][10] of p53 tumor suppressor protein.…”

“…This may explain the lower effect of prodigiosin compounds on these cells compared with the higher IC 50 values observed for the U937 cells. In these cell lines, an extrinsic apoptosis pathway which is triggered independently of p53 protein 7 may play an , the intrinsic apoptotic pathway may still be a critical mechanism for programmed cell death. Regardless, it is essential to investigate how prodigiosins may affect other pathways that are involved in the apoptosis process.…”

On the TRAIL of a new therapy for leukemia

“…21,[66][67][68] Consistent with this proposed physiological role, TRAIL is selectively cytotoxic to a wide variety of human tumor cell lines in vitro and when grown as xenografts. [69][70][71] An earlier report that TRAIL is toxic to human hepatocytes in tissue culture 72 has not been validated. 73 Likewise, agonistic anti-DR5 antibody kills neoplastic cells in vitro and in vivo, apparently without effects on normal human hepatocytes.…”

“…83 For example, DR5, which has previously been identified as the more prominent receptor involved in TRAILinduced killing of tumor cells, 84,85 is upregulated in a p53-dependent manner after DNA damage, [86][87][88] providing at least a partial explanation for the ability of DNA-damaging anticancer drugs to synergize with TRAIL in vitro and in vivo. 69,71,[87][88][89] There are other levels of regulation as well. As noted above, the recruitment of FADD by ligated death receptors 37,38 and the recruitment/activation of caspase 8 by FADD [30][31][32][33] appear to be regulated processes.…”