title: RITA enhances irradiation-induced apoptosis in p53-defective cervical cancer cells via upregulation of IRE1α/XBP1 signaling.
abstract: Radiation therapy is the most widely used treatment for patients with cervical cancer. Recent studies have shown that endoplasmic reticulum (ER) stress induces apoptosis and sensitizes tumor cells to radiotherapy, which reportedly induces ER stress in cells. Classical key tumor suppressor p53 is involved in the response to a variety of cellular stresses, including those incurred by ionizing irradiation. A recent study demonstrated that small-molecule RITA (reactivation of p53 and induction of tumor cell apoptosis) increased the radiosensitivity of tumor cells expressing mutant p53 (mtp53). In the present study, we explored the effects and the underlying mechanisms of RITA in regards to the radiosensitivity and ER stress in mtp53-expressing human cervix cancer cells. Treatment with 1 µM of RITA for 24 h before irradiation markedly decreased survival and increased apoptosis in C-33A and HT-3 cells; the effects were not significantly altered by knockdown of p53. In the irradiated C-33A and HT-3 cells, RITA significantly increased the expression of IRE1α, the spliced XBP1 mRNA level, as well as apoptosis; the effects were abolished by knockdown of IRE1α. Transcriptional pulse-chase assays revealed that RITA significantly increased the stability of IRE1α mRNA in the irradiated C-33A and HT-3 cells. In contrast, the same RITA treatment did not show any significant effect on sham-irradiated cells. In conclusion, the present study provides initial evidence that RITA upregulates the expression level of IRE1α by increasing the stability of IRE1α mRNA in irradiated mtp53-expressing cervical cancer cells; the effect leads to enhanced IRE1α/XBP1 ER stress signaling and increased apoptosis in the cells. The present study offers novel insight into the pharmacological potential of RITA in the radiotherapy for cervical cancer.
authors.affiliation: Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
authors.forename: Muyasha
authors.initials: M
authors.lastname: Abulimiti
authors.affiliation: Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
authors.forename: Xiang-Jiang
authors.initials: XJ
authors.lastname: Su
authors.affiliation: Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
authors.forename: Cai-Hong
authors.initials: CH
authors.lastname: Liu
authors.affiliation: Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
authors.forename: Hai-Ping
authors.initials: HP
authors.lastname: Pei
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D004722:Endoribonucleases / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011827:Radiation; D011836:Radiation Tolerance; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000528:radiation effects; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D000071701:Regulatory Factor X Transcription Factors; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C403666:ZNF331 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases