Abstract
Colon cancer is a major health problem worldwide. While chemotherapy remains a main approach for treating late-stage colon cancer patients, most, if not all, of them will develop drug resistance and die of uncontrollable disease progression eventually. Therefore, identification of mechanism of drug resistance and development of overcoming strategy hold great significance in management of colon cancer. In this study, we discovered that activation of the PERK branch of the unfolded protein response (UPR) pathways is required for colon cancer cells to survive treatment of 5-Fluorouracil (5-FU), one of the first-line chemotherapeutics for late-stage colon cancer patients. Genetic and pharmacological inhibition of PERK or its downstream factors greatly sensitize colon cancer cells to 5-FU. Most importantly, in vivo use of PERK inhibitor synergizes with 5-FU in suppressing the growth of colon cancer cells in mouse models. In summary, our findings established a promising way to overcome resistance to chemotherapy in colon cancer.
Highlights
Colorectal cancer (CRC) is the third most common cancer in the US, with over 146,000 new cases and almost 57,000 deaths each year, making it the second leading cause of death from cancer among adults[1]
Based on the above results, we found that the unfolded protein response (UPR) pathways are differentially activated in CRC cells
We set out to investigate the molecular mechanism of drug resistance of colon cancer cells, and discovered that activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) kinase-mediated stress signaling plays an important role in promoting cell survival under chemotherapy
Summary
Colorectal cancer (CRC) is the third most common cancer in the US, with over 146,000 new cases and almost 57,000 deaths each year, making it the second leading cause of death from cancer among adults[1]. UPR signaling is initiated by three distinct receptors localized to the ER membrane – protein kinase RNA-like endoplasmic reticulum kinase (PERK), endoplasmic reticulum-to-nucleus signaling[1] (ERN1/IRE1α), and ATF611–14. While these receptors converge on multiple shared downstream signaling molecules, including BIP, CHOP and GADD34, they have unique signaling effects: activated IRE1α induces splicing of XBP1 mRNA, resulting in the translation of a frame-shifted stable form of the protein that functions as a transcription factor (XBP1(S)); activated PERK phosphorylates eIF2α, inducing an integrated stress response associated with global translational repression and selective translation of repair proteins (e.g., ATF4). We discovered a cellular stress pathway that can confer drug resistance, and identified a potential approach to overcome chemo-resistance in human colon cancer
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