Gastrointestinal stromal tumors (GISTs) are rare tumors, which represent approximately 1% of the neoplasms of the gastrointestinal tract. These tumors rarely give extra-abdominal metastases. However, their clinical ou...Gastrointestinal stromal tumors (GISTs) are rare tumors, which represent approximately 1% of the neoplasms of the gastrointestinal tract. These tumors rarely give extra-abdominal metastases. However, their clinical outcome is potentially adverse. In some rare cases, co- existance of GISTs with other malignancies has been reported. Here we present a case of a 74-year old male with GIST, which was managed by surgical resection. Fourteen months later, the patient presented with liver metastases and imatinib mesylated was administered. During treatment, the patient reported skeletal pain and plane X-rays revealed osteolytic bone lesions. Further investigation revealed the presence of multiple myeloma. To the best of our knowledge, this is the first report of the co-existence of multiple myeloma (MM) with GIST.展开更多
Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma （MM）. While survival benefit of bortezomib generated new treatment strategies, ...Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma （MM）. While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 （Pirh2） in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM. The proteasome inhibitor bortezomib has been established as one of the most effective drugs for treating MM. We demonstrated that bortezomib resistance in MM cells resulted from a reduction in Pirh2 protein levels. Pirh2 overexpression overcame bortezomib resistance and restored the sensitivity of myeloma cells to bortezomib, while a reduction in Pirh2 levels was correlated with bortezomib resistance. The levels of nuclear factor- kappaB （NF-κB） p65, pp65, plKBa, and IKKa were higher in bortezomib-resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of plKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-κB p65, plKBa, and IKKa. Therefore, Pirh2 suppressed the canonical NF- κB signaling pathway by inhibiting the phosphorylation and subsequent degradation of IKBa to overcome acquired bortezomib resistance in MM cells.展开更多
Protein homeostasis is the basis of normal life activities,and the proteasomefamily plays an extremely important function in this process.The proteasome 2os is a concentric circle structure with twoαrings and twoβri...Protein homeostasis is the basis of normal life activities,and the proteasomefamily plays an extremely important function in this process.The proteasome 2os is a concentric circle structure with twoαrings and twoβrings overlapped.The proteasome 2os can perform both ATP-dependent and non-ATP-dependent ubiquitination proteasome degradation by binding to various subunits(such as 19S,11S,and 200 PA),which is performed by its active subunitβ1,β2,andβ5.The proteasome can degrade misfolded,excess proteins tomaintain homeostasis.At the same time,it can be utilized by tumors to degrade over-proliferate and unwanted proteins to support their growth.Proteasomes can affect the development of tumors from several aspects including tumor signaling pathways such as NF-kB and p53,cell cycle,immune regulation,and drug resistance.Proteasome-encoding genes have been found to be overexpressed in a variety of tumors,providing a potential novel target for cancer therapy.In addition,proteasome inhibitors such as bortezomib,carfilzomib,and ixazomib have been put into clinical application as the first-line treatment of multiple myeloma.More and more studies have shown that it also has different therapeutic effects in other tumors such as hepatocellular carcinoma,non-small cell lung cancer,glioblastoma,and neuroblastoma.However,proteasome inhibitors are not much effective due to their tolerance and singleness in other tumors.Therefore,further studies on their mechanisms of action and drug interactions are needed to investigate their therapeutic potential.展开更多
文摘Gastrointestinal stromal tumors (GISTs) are rare tumors, which represent approximately 1% of the neoplasms of the gastrointestinal tract. These tumors rarely give extra-abdominal metastases. However, their clinical outcome is potentially adverse. In some rare cases, co- existance of GISTs with other malignancies has been reported. Here we present a case of a 74-year old male with GIST, which was managed by surgical resection. Fourteen months later, the patient presented with liver metastases and imatinib mesylated was administered. During treatment, the patient reported skeletal pain and plane X-rays revealed osteolytic bone lesions. Further investigation revealed the presence of multiple myeloma. To the best of our knowledge, this is the first report of the co-existence of multiple myeloma (MM) with GIST.
文摘Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma （MM）. While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 （Pirh2） in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM. The proteasome inhibitor bortezomib has been established as one of the most effective drugs for treating MM. We demonstrated that bortezomib resistance in MM cells resulted from a reduction in Pirh2 protein levels. Pirh2 overexpression overcame bortezomib resistance and restored the sensitivity of myeloma cells to bortezomib, while a reduction in Pirh2 levels was correlated with bortezomib resistance. The levels of nuclear factor- kappaB （NF-κB） p65, pp65, plKBa, and IKKa were higher in bortezomib-resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of plKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-κB p65, plKBa, and IKKa. Therefore, Pirh2 suppressed the canonical NF- κB signaling pathway by inhibiting the phosphorylation and subsequent degradation of IKBa to overcome acquired bortezomib resistance in MM cells.
基金supported by the National Natural Science Foundation of China(No.82172619)the Natural Science Foundation of Chongqing,China(No.CSTC2021jscx-gksb-No023)the Medical and Industrial Integration Project(China)(No.2022CDJYGRH-002).
文摘Protein homeostasis is the basis of normal life activities,and the proteasomefamily plays an extremely important function in this process.The proteasome 2os is a concentric circle structure with twoαrings and twoβrings overlapped.The proteasome 2os can perform both ATP-dependent and non-ATP-dependent ubiquitination proteasome degradation by binding to various subunits(such as 19S,11S,and 200 PA),which is performed by its active subunitβ1,β2,andβ5.The proteasome can degrade misfolded,excess proteins tomaintain homeostasis.At the same time,it can be utilized by tumors to degrade over-proliferate and unwanted proteins to support their growth.Proteasomes can affect the development of tumors from several aspects including tumor signaling pathways such as NF-kB and p53,cell cycle,immune regulation,and drug resistance.Proteasome-encoding genes have been found to be overexpressed in a variety of tumors,providing a potential novel target for cancer therapy.In addition,proteasome inhibitors such as bortezomib,carfilzomib,and ixazomib have been put into clinical application as the first-line treatment of multiple myeloma.More and more studies have shown that it also has different therapeutic effects in other tumors such as hepatocellular carcinoma,non-small cell lung cancer,glioblastoma,and neuroblastoma.However,proteasome inhibitors are not much effective due to their tolerance and singleness in other tumors.Therefore,further studies on their mechanisms of action and drug interactions are needed to investigate their therapeutic potential.
