Blockade of ubiquitin-conjugating enzyme CDC34 enhances anti-myeloma activity of Bortezomib/Proteasome inhibitor PS-341

Chauhan, Dharminder; Li, Guilan; Hideshima, Teru; Podar, Klaus; Shringarpure, Reshma; Mitsiades, Constantine S.; Munshi, Nikhil C.; Yew, P. Renée; Anderson, Kenneth C.

doi:10.1038/sj.onc.1207458

Cited by 53 publications

(35 citation statements)

References 28 publications

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“…26 CDC34 is highly expressed in multiple myeloma (MM) and associated with the growth and survival of MM cells. 27 An immunocytochemical study showed that FZD3 is strongly associated with CRC progression. 28 Additional studies on miR-4500 and its target genes may be helpful for understanding tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

Yun

Deng

et al. 2016

Cancer Biology & Therapy

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This study aimed to understand the exact function and potential mechanism of miR-4500 in colorectal cancer (CRC). In this study, the expression of miR-4500 was decreased in both CRC cells and tissues, and downregulated miR-4500 indicated advanced tumor stage and poor survival. By bisulfite sequencing analysis, we found that the CpG island in the promoter region of miR-4500 was hypermethylated in CRC cells and tissues compared with normal control cells and non-tumor tissues, respectively. Functionally, gain-and loss-of-function analyses indicated the tumor suppressor role of miR-4500: it suppressed cell proliferation, cell cycle progression, migration, and invasion. Predictive algorithms and experimental analyses identified HMGA2 as a direct target of miR-4500. Reintroducing HMGA2 impaired the inhibitory effects of miR-4500 on cell growth and motility. Clinically, higher HMGA2 protein expression in CRC tissues was associated with advanced tumor stage and poor survival. An inverse correlation was found between miR-4500 levels and HMGA2 protein expression. Taken together, this study provides the first evidence that miR-4500 functions as a novel tumor suppressor in the miR-4500/HMGA2 axis in colorectal carcinogenesis, and restoring miR-4500 expression might represent a promising therapeutic strategy for CRC.Abbreviations: CRC, Colorectal cancer; HMGA2, high mobility group AT-hook 2; 5-aza, 5-aza-2 0 -deoxycytidine

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Section: Discussionmentioning

confidence: 99%

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

Yun

Deng

et al. 2016

Cancer Biology & Therapy

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“…Dex, 2ME2, and PS-341 treatments are associated with decreased CDC34 expression. Blocking CDC34 augments sensitivity to these therapies [67]. Targeting mitochondria may be an effective way to overcome conventional resistance and Velcade resistance in MM [68].…”

Section: Growth and Survival Factors Prevent Apoptosismentioning

confidence: 99%

Apoptosis of Multiple Myeloma

Oancea

Mani²,

Hussein³

et al. 2004

International Journal of Hematology

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Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells. MM cells localize to the bone marrow, where cell adhesion-mediated autocrine or paracrine activation of various cytokines, such as interleukin 6, insulin-like growth factor 1, and interferon α, results in their accumulation mainly because of loss of critical apoptotic controls. Resistance to apoptosis, a genetically regulated cell death process, may play a critical role in both pathogenesis and resistance to treatment of MM. Abnormalities in regulation and execution of apoptosis can contribute to tumor initiation, progression, as well as to tumor resistance to various therapeutic agents. Apoptosis is executed via 2 main pathways that lead to activation of caspases: the death receptor (extrinsic) pathway and the mitochondrial (intrinsic) pathway. Ionizing radiation and chemotherapeutic agents act primarily through the intrinsic pathway, in which mitochondria play the central role. Various therapeutic modalities that are effective in MM modulate levels of the proapoptotic and antiapoptotic Bcl-2 family of proteins and of inhibitors of apoptosis, expression of which is primarily regulated by p53, nuclear factor κB, and STAT (signal transducers and activators of transcription) factors. This review focuses on the key concepts and some of the most recent studies of signaling pathways regulated in MM and summarizes what is known about the clinical role of these pathways.

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“…Multiple myeloma is the most sensitive and the most responsive disease to proteasomal inhibitors, which implies that the UPP is critical for multiple myeloma pathophysiology. E1 [4], E2s such as CDC34 [5], E3s such as Mdm-2 [6] and SCF [7], and DUBs such as USP9X [8] are overexpressed and involved in multiple myeloma pathology. Furthermore, targeting such UPP components could sensitize MM cells susceptible to bortezomib-induced cell death [4,7].…”

Section: Introductionmentioning

confidence: 99%

Curcusone D, a novel ubiquitin–proteasome pathway inhibitor via ROS-induced DUB inhibition, is synergistic with bortezomib against multiple myeloma cell growth

Cao

Zhou

Gao

et al. 2014

Biochimica et Biophysica Acta (BBA) - General Subjects

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Blockade of ubiquitin-conjugating enzyme CDC34 enhances anti-myeloma activity of Bortezomib/Proteasome inhibitor PS-341

Cited by 53 publications

References 28 publications

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

Apoptosis of Multiple Myeloma

Curcusone D, a novel ubiquitin–proteasome pathway inhibitor via ROS-induced DUB inhibition, is synergistic with bortezomib against multiple myeloma cell growth

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