Proteomic and Functional Analyses Reveal a Dual Molecular Mechanism Underlying Arsenic-Induced Apoptosis in Human Multiple Myeloma Cells

Ge, Feng; Lu, Xinpeng; Zeng, Huilan; He, Quanyuan; Xiong, Sheng; Jin, Lin; He, Qing‐Yu

doi:10.1021/pr9001004

Cited by 51 publications

(63 citation statements)

References 43 publications

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“…These data suggest that YWHAZ could be a preferential target for both MMECs and MM plasma cells as demonstrated previously (Ge et al, 2009), whereas the other proteins should be characterized in each patient to target plasma cells.…”

Section: Angiogenic Proteins Of Mmecs S Berardi Et Alsupporting

confidence: 79%

Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

et al. 2011

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Bone marrow (BM) angiogenesis has an important role in the initiation and progression of multiple myeloma (MM). We looked at novel mechanisms of vessel formation in patients with MM through a comparative proteomic analysis between BM endothelial cells (ECs) of patients with active MM (MMECs) and ECs of patients with monoclonal gammopathy of undetermined significance (MGECs) and of subjects with benign anemia (normal ECs). Four proteins were found overexpressed in MMECs: filamin A, vimentin, a-crystallin B and 14-3-3f/d protein, not yet linked to overangiogenic phenotype. These proteins gave a typical distribution in the BM of MM patients and in MMECs versus MGECs, plausibly according to a different functional state. Their expression was enhanced by vascular endothelial growth factor, fibroblast growth factor 2, hepatocyte growth factor and MM plasma cell conditioned medium in step with enhancement of MMEC angiogenesis. Their silencing RNA knockdown affected critical MMEC angiogenesis-related functions, such as spreading, migration and tubular morphogenesis. A gradual stabilization of 14-3-3f/d protein was observed, with transition from normal ECs to MGECs and MMECs that may be a critical step for the angiogenic switch in MMECs and maintenance of the cell overangiogenic phenotype. These proteins were substantially impacted by anti-MM drugs, such as bortezomib, lenalidomide and panobinostat. Results suggest that these four proteins could be new targets for the antiangiogenic management of MM patients.

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Section: Angiogenic Proteins Of Mmecs S Berardi Et Alsupporting

confidence: 79%

Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

et al. 2011

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“…The third densest cluster (cluster 3) is composed of several key components of the proteasome (Fig. S3B), suggesting that arsenic may disturb the proper functioning of the proteasome, as previously proposed (9).…”

Section: Bioinformatics Analysis Reveals a Striking Enrichment Of Glysupporting

confidence: 77%

“…Ge et al (9) monitored global changes in protein expression in a multiple myeloma cell line treated with arsenic. The most significant changes were observed for carbohydrate metabolism and nucleotide metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…A variety of systematic studies, including studies that provided transcriptomic, chemogenomic, or proteomic characterizations (8,9), have been performed to gain a better understanding of this broader anticancer activity of ATO. However, these studies examined only the cellular consequences of treatment with ATO without identifying the primary proteins directly bound and modulated by ATO.…”

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confidence: 99%

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Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic

Zhang

Yang

Ling

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Arsenic is highly effective for treating acute promyelocytic leukemia (APL) and has shown significant promise against many other tumors. However, although its mechanistic effects in APL are established, its broader anticancer mode of action is not understood. In this study, using a human proteome microarray, we identified 360 proteins that specifically bind arsenic. Among the most highly enriched proteins in this set are those in the glycolysis pathway, including the rate-limiting enzyme in glycolysis, hexokinase-1. Detailed biochemical and metabolomics analyses of the highly homologous hexokinase-2 (HK2), which is overexpressed in many cancers, revealed significant inhibition by arsenic. Furthermore, overexpression of HK2 rescued cells from arsenic-induced apoptosis. Our results thus strongly implicate glycolysis, and HK2 in particular, as a key target of arsenic. Moreover, the arsenic-binding proteins identified in this work are expected to serve as a valuable resource for the development of synergistic antitumor therapeutic strategies.arsenic trioxide | human proteome microarray | glycolysis | hexokinase-2IA rsenic and its derivatives have been applied as therapy for a variety of diseases for more than 2,200 y (1). To date, the disease most successfully treated with these types of compounds is acute promyelocytic leukemia (APL). Administration of arsenic trioxide (ATO) combined with all-trans retinoic acid has demonstrated a remarkable 5-y overall survival rate of 85-90% as a consequence of the dramatic down-regulation of the key protein driving APL tumorigenicity, promyelocytic leukemia-retinoic acid receptor α (PML-RARα) (2). However, ATO also has been found to be effective against many other hematologic malignancies and solid tumors. For example, together with imatinib it is a promising treatment for chronic myelocytic leukemia (3), and it has been used alone with some success to treat multiple myeloma (4), myelodysplasia syndrome (5), and non-Hodgkin lymphoma (6). ATO also is under clinical investigation as a possible medication for lung cancer, hepatocellular carcinoma, melanoma, renal cell carcinoma, and colorectal cancer (https://www.clinicaltrials.gov/). At the cellular level, ATO has been shown to inhibit significantly the growth of almost all the cell lines (59 of 60) in the US National Cancer Institute anticancer drug screen that spans nine different tumor types (7). Thus ATO is one of the most promising broadly effective medications against cancer.Although its mode of action in APL is well established, the underlying mechanisms by which ATO acts in other types of cancers remain poorly understood. A variety of systematic studies, including studies that provided transcriptomic, chemogenomic, or proteomic characterizations (8, 9), have been performed to gain a better understanding of this broader anticancer activity of ATO. However, these studies examined only the cellular consequences of treatment with ATO without identifying the primary proteins directly bound and modulated by ATO. Knowledge of ATO...

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“…[24][25][26][27][28] In recent years, different proteomic approaches have been taken to investigate various aspects of MM and have provided new insights into the pathogenesis of MM. [29][30][31] In this study, the SILAC method was employed to compare the protein profiles of parental MM cells and revertants. In total, 379 differentially expressed proteins (DEPs) were identified, most of which interact in some way with STAT3, suggesting that the STAT3 pathway may play a vital role in myeloma reversion.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Proteomic Analysis of Tumor Reversion in Multiple Myeloma Cells

Zhang

Tao

et al. 2010

J. Proteome Res.

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Tumor reversion is defined as the process by which cancer cells lose their malignant phenotype. However, relatively little is known about the cellular proteome changes that occur during the reversion process. A biological model of multiple myeloma (MM) reversion was established by using the H-1 parvovirus as a tool to select for revertant cells from MM cells. Isolated revertant cells displayed a strongly suppressed malignant phenotype both in vitro and in vivo. To explore possible mechanisms of MM reversion, the protein profiles of the revertant and parental MM cells were compared using a quantitative proteomic strategy termed SILAC-MS. Our results revealed that 379 proteins were either activated or inhibited during the reversion process, with a much greater proportion of the proteins, including STAT3, TCTP, CDC2, BAG2, and PCNA, being inhibited. Of these, STAT3, which is significantly down regulated, was selected for further functional studies. Inhibition of STAT3 expression by RNA interference resulted in suppression of the malignant phenotype and concomitant down regulation of TCTP expression, suggesting that myeloma reversion operates, at least in part, through inhibition of STAT3. Our results provide novel insights into the mechanisms of tumor reversion and suggest new alternative approaches for MM treatment.

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Proteomic and Functional Analyses Reveal a Dual Molecular Mechanism Underlying Arsenic-Induced Apoptosis in Human Multiple Myeloma Cells

Cited by 51 publications

References 43 publications

Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic

Quantitative Proteomic Analysis of Tumor Reversion in Multiple Myeloma Cells

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