Research Article: Lymphoma and Myeloma Cell Resistance to Cytotoxic Agents and Ionizing Radiations Is Not Affected by Exposure to Anti–IL-6 Antibody

Date Published: November 30, 2009

Publisher: Public Library of Science

Author(s): Angélique Gougelet, Adeline Mansuy, Jean-Yves Blay, Laurent Alberti, Claudine Vermot-Desroches, Andy T. Y. Lau.

Abstract: Production of high levels of IL-6 is often correlated with resistance to cytotoxics or ionizing radiations, in cancer cell lines as in various cancer patients. We investigated whether monoclonal antibodies directed against IL-6 may enable to reverse resistance of cancer cell lines.

Partial Text: Interleukin-6 (IL-6) is a key cytokine mainly produced by a broad variety of cell types including monocytes, fibroblasts, endothelial cells, and epithelial as haematological tumour cell lines [1]. IL-6 is particularly involved in immune response, inflammation and in haematopoiesis by controlling proliferation and maturation of B and T cells and differentiation of cytotoxic T cells, macrophages and megakaryocytes. Besides, IL-6 promotes the proliferation of haematological malignancies (leukemia, lymphoma and myeloma), and solid tumours (breast and renal adenocarcinoma or Kaposi sarcoma) [1], [2], through an intracrine, autocrine and paracrine mode of action [3], [4]. Finally, a high IL-6 serum level is often associated to worse progression-free survival and overall survival in Non Hodgkin Lymphoma [5], myeloma [6], renal carcinoma and breast adenocarcinoma [7], [8].

This study revealed that a potent correlation exists between IL-6 expression by oncohaematologic cells and their resistance to conventional treatments: U266, BL-36, Daudi and Namalwa cells expressing IL-6 constitute the most resistant cells to radiations and doxorubicin (Table 1 and Figure S1, S2). IL-6 inhibition successfully interfered with IL-6 induced cell signaling pathways in U266 and U937 cells, and particularly reduced STAT3 phosphorylation on Tyr705, on its own and in the presence of doxorubicin as cisplatin, or following irradiation at 7Gy (Figure 2 and Figure 4). In contrast, IL-6 inhibition marginally affected the level of p-STAT3 on Ser727. The function of this phosphorylated residue is always nowadays much debated: some labs suggested that this phosphorylation was required for STAT homo-dimerization and DNA binding [38], contrary to others supporting its role for the transcriptional activation of its targets through its association with Pin1 and p300 [39], [40]. Chung et. al showed that the phosphorylation of STAT3 on Ser727 is due to p42/p44 and that an inverse correlation between Ser727 phosphorylation and that on Tyr 705 exists [41]. Although p-p42/p44 level was impaired through IL-6 inhibition in U266 and Daudi cells (Figure 2A and Figure 3, respectively), the level of p-STAT3-Ser727 was increased in U266 cells after 30 and 60 min exposure to IL-6, but was also elevated in U266 and U937 cells following radiation or chemotherapy treatments (Figure 4). This suggests that 1) other kinases than p42/p44 regulate STAT3 phosphorylation on Ser727 in our models, and that 2) this hyperphosphorylated form of STAT3 could be more active for the transcription of its targets.



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