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The Study of Effect and Related Mechanism of IL-6 Induced Ovarian Cancer Cells Resistance to Chemotherapy

Author: WuJian
Tutor: LiLingZhi；WangYue
School: Hebei Medical University
Course: Pharmacology
Keywords: Interleukin-6 Ovarian cancer Resistance to chemotherapy Resistance gene Anti-apoptotic gene
CLC: R737.31
Type: Master's thesis
Year: 2010
Downloads: 49
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Abstract


Objective: The incidence of ovarian cancer occult, most patients are diagnosed at advanced stage, the treatment is radical cytoreductive surgery and cisplatin and paclitaxel-based combination chemotherapy, but the long-term effect is not very ideal, resistant occurs the main factors restricting the clinical treatment. In recent years, studies have shown that interleukin-6 (Interleukin6, IL-6) highly expressed in ovarian cancer cells, IL-6 not only play an important role in the occurrence and development of ovarian cancer, but also affect the ovarian cancer cells sensitive to chemotherapeutic drugs sex. On IL-6 in ovarian cancer chemotherapy resistance and its mechanism is not yet clear, the subject of the first observation of the IL-6 expression in ovarian cancer resistance to chemotherapy, on the basis of its mechanism and related signaling pathway was discussed. Methods: enzyme-linked immunosorbent assay (enzyme linked immunosorbent assay, ELISA), immunoblotting (Western Blot), reverse transcription-polymerase chain reaction (the Reverse transcription polymerase chain Reaction, RT-PCR) and MTT assay, the four international universally recognized human epithelial ovarian cancer cell lines, IL-6 and its receptor (IL-6Rα, gp130) expression levels and their chemosensitivity and resistance-associated genes and apoptosis gene expression levels were analyzed. On this basis, we choose not to secrete IL-6 but the expression of its receptor, A2780 cells sensitive to cisplatin and paclitaxel and high expression of IL-6 and its receptor, cisplatin and paclitaxel-resistant SKOV3 cells for the study of model : (1) MTT assay and RT-PCR of exogenous IL-6 would not affect the sensitivity of A2780 cells to cisplatin and paclitaxel resistance-associated genes and apoptosis inhibition gene expression; (2) liposome containing justice (SENSE, SS) or antisense (antisense, as) IL-6 cDNA expression vectors were transfected into A2780 and SKOV3 cells, application G418 positive clones were identified by ELISA . Using the same method as described above stable cell clones expressing ss/asIL-6 cisplatin and paclitaxel sensitivity and resistance-associated genes and expression of apoptosis gene detection; (3) application-specific signal blocker PD98059 (MEK1 / 2 inhibitor) and wortmannin (PI3K inhibitor), were observed in of its exogenous IL-6 or over-expression of endogenous IL-6 induced ovarian cancer cell resistance to chemotherapy blocking effect. Results: (1) four ovarian cancer cell except A2780 cells constitutively secrete IL-6, substantially consistent with the transcriptional level and protein level, and the expression of IL-6 receptor (IL-6Rα, gp130); (2) four ovarian cancer cell sensitivity to cisplatin and paclitaxel, which is the most sensitive A2780 cells, ES-2 cells, followed by CAOV-3 and SKOV-3 cells with different degrees of resistance; (3) of the resistance related gene lower average gene expression levels in the A2780 and ES-2 cells and inhibition of apoptosis, CAOV-3 and SKOV-3 cells in higher expression levels. (4) exogenous IL-6 can significantly reduce the sensitivity of A2780 cells to cisplatin and paclitaxel, and a dose-dependent increase in resistance gene MDR1 and GST-pi and inhibitor of apoptosis gene Bcl-2, Bcl- xL, XIAP expression; (5) Filter IL-6, high expression of A2780 clone, named A2780/ssIL-6L A2780/ssIL-6M, A2780/ssIL-6H, and IL-6 in high inhibit the expression of SKOV3 clones were named the SKOV3/asIL-6MI, SKOV3/asIL-6HI, and the corresponding empty vector pcDNA3.1 () / A2780 and pcDNA3.1 () / SKOV3 clone; (6) and empty vector pcDNA3.1 () / A2780 and A2780 cells compared to non-transfected SSIL-6 gene transfected cells sensitivity to cisplatin and paclitaxel significantly reduced, the drug-related genes and apoptosis suppressor gene expression levels significantly increased; (7) with the empty vector pcDNA3.1 () / SKOV3 and non-transfected SKOV3 cells the ASIL-6 gene transfected cells sensitivity to cisplatin and paclitaxel significantly increased, the resistance related genes and apoptosis inhibition of gene expression levels were significantly lower; (8) specific signal blocker PD98059 and wortmannin blocking a dose-dependent manner by the endogenous expression of exogenous IL-6 or IL- 6 induced ovarian cancer cells resistant to cisplatin and paclitaxel. Conclusions: (1) ovarian cancer cells by autocrine IL-6 can be induced to become resistant to traditional chemotherapy drug cisplatin and paclitaxel; (2) IL-6 induced ovarian cancer cells to chemotherapy resistance may increase resistance drug-related gene MDR1, GST-pi and apoptosis inhibiting gene Bcl-2, Bcl-xL and XIAP expression related; (3) IL-6, at least through the activation of the Ras / Raf / MEK / ERK and PI3K/Akt signaling pathway ovarian cancer cells to induce resistance to chemotherapy.

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CLC: > Medicine, health > Oncology > Genitourinary tumors > Female genital tumors > Ovarian tumors
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