REGULATION OF TGF-ß SIGNALLING BY NUCLEAR RECEPTOR CO-REPRESSOR (N-COR) IN GASTRIC CANCER CELLS

Abstract

TGF-ß signaling plays an important role in cell-fate determination by dynamically regulating the transcription of genes involved in cell proliferation, differentiation and apoptosis. Many of these processes are regulated by precise transcriptional control imparted by factors like N-CoR. Acquired resistance to TGF-ß-induced apoptosis is an important feature of many human malignancies including gastric cancer. Artemisinin has been shown to block the growth of colorectal cells through inhibiting the hyperactive Wnt/ß-catenin pathway. Since TGF-ß is known to antagonize the growth promoting signal of Wnt pathway, it was hypothesized that growth suppressive effect of artemisinin might also involve the activation of TGF-ß signaling. Indeed, screening of a selected group of synthetic artemisinin analogues in various gastric cancer derived cell lines identified an artemisinin derivative GC011 that selectively inhibited the growth and promoted apoptosis of TGF-ß sensitive gastric cancer cells. This sensitivity to GC011 was dependent on N-CoR degradation, facilitated by ubiquitination induced by the transcription factor RUNX3. These findings highlight the therapeutic potential of GC011 in TGF-ß sensitive gastric cancer cells. However, as N-CoR was observed to be misfolded in GC011 and TGF-ß resistant gastric cancer cells, targeting the N-CoR misfolding pathway may break the barrier of TGF-ß resistance and sensitize the cancer cells to apoptosis. As cellular response to the accumulation of misfolded proteins involves the activation of the UPR pathway, it was postulated that blocking the loss of misfolded N-CoR with proteasome inhibitor would sensitize the gastric cancer cells to ER-stress induced apoptosis. Interestingly, the proteosome inhibitor bortezomib effectively sensitized the gastric cancer cells to ER stress-induced apoptosis by promoting the accumulation of misfolded N-CoR via inhibition of its proteosomal degradation by the ERAD pathway. These findings suggest that gastric cancer cells have a low threshold for proteosomal inhibitor-induced UPR activation and ER stress-induced apoptosis, and also demonstrate the therapeutic potential of proteasome inhibitors such as bortezomib in the treatment of gastric cancer.