Abstract
Interleukin-6 (IL6)-triggered JAK/STAT3 and PI3K/AKT signaling pathways are known to mediate cell survival, drug resistance and progression in a variety of cancer cells. Resistance to induction of apoptosis plays a critical role in the pathogenesis of numerous cancers and development of resistance to chemotherapeutic agents used in its treatment. Previous research in our laboratory employing a dexamethasone-resistant subline (7TD1-Dxm) of IL6-dependent 7TD1 cells indicated that constitutively activated STAT3 was important in control of apoptosis and targets downstream to activated STAT3 appeared to be involved in the development of resistance to dexamethasone by 7TD1 cells. We therefore investigated the hypothesis that Dxm-resistance developed by 7TD1-Dxm cells was due to resistance to induction of apoptosis mainly because of the dysregulation of the downstream targeted in JAK/STAT3 signaling pathway. Our results indicate that 7TD1-Dxm cells show resistance to Dxm-induced reduction of Bcl-2 protein and the release of cytochrome c. Thus, this study suggests that development of resistance to dexamethasone by 7TD1 cells may involve altered regulation of mitochondrial anti-apoptotic proteins.
Highlights
Interleukin-6 (IL6) is a pleiotropic cytokine involved in the progression of various cancers like colon, pancreatic and prostate cancers and multiple myeloma (MM) [1,2,3,4,5,6,7]
Previous research in our laboratory employing a dexamethasone-resistant subline (7TD1-Dxm) of IL6-dependent 7TD1 cells indicated that constitutively activated STAT3 was important in control of apoptosis and targets downstream to activated STAT3 appeared to be involved in the development of resistance to dexamethasone by 7TD1 cells
We examined the effect of dexamethasone on cytochrome c release from mitochondria into the cytoplasm which is a downstream event that occurs after reduction of Bcl-2 protein
Summary
Interleukin-6 (IL6) is a pleiotropic cytokine involved in the progression of various cancers like colon, pancreatic and prostate cancers and multiple myeloma (MM) [1,2,3,4,5,6,7]. IL6 promotes cell proliferation and protects from dexamethasone (Dxm)-induced apoptosis by triggering three main signaling pathways including JAK/STAT3, PI3K/AKT, and MAPK signaling pathways [8,9,10,11]. These factors contribute to the cells’ development of resistance to a variety of chemotherapeutic agents. The Bcl-2 family of anti-apoptotic proteins, including Bcl-2, Bcl-XL and Mcl-1, are known to be over-expressed and to play an important role in cell survival and development of resistance to chemotherapeutic agents like dexamethasone [12,13,14,15,16,17]. Activation of STAT3 by phosphorylation promotes the transcriptional activation of Bcl-2 family proteins including Bcl-2, Bcl-XL and Mcl-1 [16,18,19,20,21]
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