| Autor: |
Chern YJ; Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.; Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver, British Columbia, Canada., Wong JCT; Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.; Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver, British Columbia, Canada., Cheng GSW; Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.; Department of Medical Genetics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada., Yu A; Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.; Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver, British Columbia, Canada., Yin Y; Cancer Surveillance & Outcomes, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.; Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada., Schaeffer DF; Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada., Kennecke HF; Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada., Morin G; Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.; Department of Medical Genetics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada., Tai IT; Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. itai@bcgsc.ca.; Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. itai@bcgsc.ca. |
| Abstrakt: |
Therapy-refractory disease is one of the main contributors of treatment failure in cancer. In colorectal cancer (CRC), SPARC can function as a sensitizer to conventional chemotherapy by enhancing apoptosis by interfering with the activity of Bcl-2. Here, we examine a novel mechanism by which SPARC further potentiates apoptosis via its modulation of the unfolded protein response (UPR). Using mass spectrometry to identify SPARC-associated proteins, GRP78 was identified as a protein partner for SPARC in CRC. In vitro studies conducted to assess the signaling events resulting from this interaction, included induction of ER stress with tunicamycin, 5-fluorouracil (5-FU), and irinotecan (CPT-11). We found that the interaction between GRP78 and SPARC increased during exposure to 5-FU, CPT-11, and tunicamycin, resulting in an attenuation of GRP78's inhibition of apoptosis. In addition, we also show that SPARC can sensitize CRC cells to PERK/eIF2α and IRE1α/XBP-1 UPR signaling by interfering with ER stress following binding to GRP78, which leads to ER stress-associated cell death in CRC cells. In line with these findings, a lower expression of GRP78 relative to SPARC in CRC is associated with a lower IC 50 for 5-FU in either sensitive or therapy-refractory CRC cells. Interestingly, this observation correlates with tissue microarray analysis of 143 human CRC, where low GRP78 to SPARC expression level was prognostic of higher survival rate (P = 0.01) in individuals with CRC. This study demonstrates that modulation of UPR signaling by SPARC promotes ER stress-associated death and potentiates apoptosis. This may be an effective strategy that can be combined with current treatment options to improve therapeutic efficacy in CRC. |
