GRP78 confers the resistance to 5-FU by activating the c-Src/LSF/TS Axis in hepatocellular carcinoma
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Yan-jiao Gu1,*, Hong-dan Li2,*, Liang Zhao2, Song Zhao3, Wu-bin He1, Li Rui1, Chang Su4, Hua-chuan Zheng5 and Rong-jian Su2
1 Pathology Department, The First Affiliated Hospital of Liaoning Medical College, Jinzhou, China
2 Central Laboratory, Liaoning Medical College, Jinzhou, China
3 Pharmacy Department, Liaoning Medical College, Jinzhou, China
4 Veterinary Medicine Department, Liaoning Medical College, Jinzhou, China
5 Cancer Research Center, Key Laboratory of Brain and Spinal Cord Injury of Liaoning Province and Laboratory Animal Center, The First Affiliated Hospital of Liaoning Medical College, Jinzhou, China
* These authors have contributed equally to this work
Rong-jian Su, email:
Keywords: GRP78, chemoresistance, 5-FU, LSF, TS
Received: April 16, 2015 Accepted: August 26, 2015 Published: September 10, 2015
5-FU is a common first-line chemotherapeutic drug for the treatment of hepatocellular carcinoma. However the development of acquired resistance to 5-FU confines its clinical usages. Although this phenomenon has been the subject of intense investigation, the exact mechanism of acquired resistance to 5-FU remains elusive. Here, we report that over-expression of GRP78 contributes to acquired resistance to 5-FU in HCC by up-regulating the c-Src/LSF/TS axis. Moreover, we found that the resistance to 5-FU conferred by GRP78 is mediated by its ATPase domain. The ATPase domain differentially increased the expression of LSF, TS and promoted the phosphorylation of ERK and Akt. We further identified that GRP78 interacts physically with c-Src through its ATPase domain and promotes the phosphorylation of c-Src, which in turn increases the expression of LSF in the nucleus. Together, GRP78 confers the resistance to 5-FU by up-regulating the c-Src/LSF/TS axis via its ATPase domain.
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