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Mechanisms of therapy-resistance modulated by GRP78, SPARC and HSP47 in colorectal cancer Chern, Yi-Jye

Abstract

Colorectal cancer (CRC) is the third leading cause of cancer mortality worldwide. The primary cause of treatment failure is the emergence of drug resistance in CRC following chemotherapy. Therefore, understanding the molecular mechanisms underlying chemoresistance in CRC is necessary for the development of effective anti-cancer therapy. We previously identified matricellular protein SPARC as a chemosensitizing agent that promotes apoptosis in CRC chemotherapy. To further understand the mechanisms by which SPARC exerts its chemosensitizing functions in CRC cells, we conducted immunoprecipitation followed by tandem mass spectrometry (MS/MS) analysis and identified GRP78- an endoplasmic reticulum (ER)- resident stress modulator- as a putative binding protein of SPARC. We found that SPARC is able to sensitize CRC cells under chemotherapy to ER stress-associated death by lowering the activation threshold of ER stress signaling via its interaction with GRP78. Notably, it was observed that a relatively higher ratio of GRP78 to SPARC expression correlated to shorter overall survival in patients with CRC, suggesting this finding is relevant clinically. Another SPARC-binding protein identified in the MS/MS analysis was ER-resident protein HSP47. As HSP47 is mostly unexplored in cancer, we focused on understanding the biology behind the role of HSP47 in CRC, especially its effects in relation to the chemotherapeutic response. We found that HSP47 is upregulated in CRC human tissues, and the expression of HSP47 promotes the resistance in CRC cells exposed to 5-fluorouracil (5-FU) by inhibiting apoptosis. In addition, overexpression of HSP47 also enhances Akt signaling in CRC cells exposed to chemotherapy by decreasing the protein stability of the Akt-specific phosphatase PHLPP1. Importantly, this finding was also confirmed in vivo as tumors with HSP47 overexpression were shown to be more resistant to 5-FU exposure and have elevated level of Akt activation. Taken together, our studies suggest a complex protein network surrounding SPARC that modulates the treatment response of CRC following chemotherapy. Therapeutic approaches against HSP47 or targeting GRP78 via SPARC mimetics may improve chemotherapeutic efficacy in CRC.

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