title: The interplay between GRP78 expression and Akt activation in human colon cancer cells under celecoxib treatment.
abstract: It has been reported previously that celecoxib shows antitumor effects in many types of cancers. Here, we detected its effects on DLD-1 and SW480 (two human colon cancer cell lines) and investigated the dynamic relationship between the 78-kDa glucose-regulatory protein (GRP78) and the phosphoinositide 3-kinase (PI3K)/Akt pathway. Gene expression was detected by real-time PCR and western blot analysis; the cytotoxicity was determined by the MTT assay and flow cytometry. First, the results showed that celecoxib induced cytotoxicity in a dose-dependent and time-dependent manner. Furthermore, we found the celecoxib-triggered unfolded protein response and the bidirectional regulation of Akt activation in both cell lines. Inhibiting the Akt activation by the PI3K inhibitor LY294002 markedly enhanced GRP78 expression. Besides, silencing the GRP78 expression regulated Akt activation in a time-dependent manner and increased the induction of the C/EBP homologous protein (CHOP) as well as considerably promoted celecoxib-induced apoptosis. In conclusion, these findings provide evidence that under the celecoxib treatment, GRP78 plays a protective role by modulating Akt activation and abrogating CHOP expression. However, Akt activation can provide a feedback loop to inhibit GRP78 expression. These studies can lead to novel therapeutic strategies for human colon cancer.
authors.affiliation: aDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan bDepartment of General Surgery, People's Hospital, Cangzhou, Hebei cDepartment of Gastroenterology, the Central Hospital of Panjin, Liaoning, People's Republic of China.
authors.forename: Shaobo
authors.initials: S
authors.lastname: Tian
authors.forename: Weilong
authors.initials: W
authors.lastname: Chang
authors.forename: Hansong
authors.initials: H
authors.lastname: Du
authors.forename: Jie
authors.initials: J
authors.lastname: Bai
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Sun
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Guangsheng
authors.initials: G
authors.lastname: Zhu
authors.forename: Kaixiong
authors.initials: K
authors.lastname: Tao
authors.forename: Yueping
authors.initials: Y
authors.lastname: Long
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000068579:Celecoxib; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D003110:Colonic Neoplasms; D000091342:Endoplasmic Reticulum Chaperone BiP; D020868:Gene Silencing; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D051742:Transcription Factor CHOP; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; D000068579:Celecoxib