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 cr...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.展开更多
Several factors could contribute to proliferation of multiple myeloma (MM) cells independent of interleukin-6 (IL6) in the later stages of the disease. Our previous studies established a dexamethasone-resistant 7TD1 c...Several factors could contribute to proliferation of multiple myeloma (MM) cells independent of interleukin-6 (IL6) in the later stages of the disease. Our previous studies established a dexamethasone-resistant 7TD1 cell line (7TD1-Dxm) and have shown that one mechanism of resistance to dexamethasone is due to inhibition of cytochrome c release. We have also observed that 7TD1-Dxm cells proliferate independently of externally-added IL6. This study therefore aimed to elucidate the mechanisms responsible for IL6-independent proliferation in 7TD1-Dxm cells. Our results indicated that 7TD1-Dxm cells produced IL6 in an autocrine fashion. We have observed that dexamethasone-resistant 7TD1 cells become dexamethasone-resistant and IL6-independent for proliferation concomitantly. This strongly suggests that production of IL6 by 7TD1-Dxm cells may play an important role in the development of dexamethasone resistance. Consequently, further investigation of the molecular mechanisms responsible for IL6 production may be helpful in delineating the mechanisms leading to dexamethasone resistance.展开更多
基金Supported by National basic research program of China,also called 973 program(2006CB933300)The cultivation fund of key scientific and technical innovation project, ministry of education of China (706035)
文摘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.
文摘Several factors could contribute to proliferation of multiple myeloma (MM) cells independent of interleukin-6 (IL6) in the later stages of the disease. Our previous studies established a dexamethasone-resistant 7TD1 cell line (7TD1-Dxm) and have shown that one mechanism of resistance to dexamethasone is due to inhibition of cytochrome c release. We have also observed that 7TD1-Dxm cells proliferate independently of externally-added IL6. This study therefore aimed to elucidate the mechanisms responsible for IL6-independent proliferation in 7TD1-Dxm cells. Our results indicated that 7TD1-Dxm cells produced IL6 in an autocrine fashion. We have observed that dexamethasone-resistant 7TD1 cells become dexamethasone-resistant and IL6-independent for proliferation concomitantly. This strongly suggests that production of IL6 by 7TD1-Dxm cells may play an important role in the development of dexamethasone resistance. Consequently, further investigation of the molecular mechanisms responsible for IL6 production may be helpful in delineating the mechanisms leading to dexamethasone resistance.
