Colorectal cancer is the third leading cause of
cancer-related mortality in the world--the main cause of death from
colorectal cancer is hepatic
metastases, which can be treated with isolated hepatic perfusion (IHP). Searching for the most clinically relevant approaches for treating colorectal metastatic disease by isolated hepatic perfusion (IHP), we developed the application of
oxaliplatin concomitantly with
hyperthermia and humanized
death receptor 4 (DR4) antibody
mapatumumab (Mapa), and investigated the molecular mechanisms of this multimodality treatment in human
colon cancer cell lines CX-1 and HCT116 as well as human
colon cancer stem cells Tu-12, Tu-21 and Tu-22. We showed here, in this study, that the synergistic effect of the multimodality treatment-induced apoptosis was
caspase dependent and activated death signaling via both the extrinsic apoptotic pathway and the intrinsic pathway. Death signaling was activated by
c-Jun N-terminal kinase (JNK) signaling which led to Bcl-xL phosphorylation at
serine 62, decreasing the anti-apoptotic activity of Bcl-xL, which contributed to the intrinsic pathway. The downregulation of cellular
FLICE inhibitory protein long
isoform (c-FLIPL) in the extrinsic pathway was accomplished through ubiquitination at
lysine residue (K) 195 and
protein synthesis inhibition. Overexpression of c-FLIPL mutant (K195R) and Bcl-xL mutant (S62A) completely abrogated the synergistic effect. The successful outcome of this study supports the application of multimodality strategy to patients with colorectal hepatic
metastases who fail to respond to standard
chemoradiotherapy that predominantly targets the mitochondrial apoptotic pathway.