Bortezomib Treatment can Overcome Glucocorticoid Resistance in Childhood B-cell Precursor Acute Lymphoblastic Leukemia Cell Lines

Junk, Stefanie V.; Cario, Gunnar; Wittner, Nicole; Stanulla, Martin; Scherer, Ralph; Schlegelberger, Brigitte; Schrappe, Martin; Neuhoff, Nils von; Lauten, Melchior

doi:10.1055/s-0034-1398628

Cited by 9 publications

(5 citation statements)

References 34 publications

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“…Furthermore, higher levels of VCP/p97 were identified in poor vs. good prednisone responders by analyzing leukemic blasts in patients with childhood acute lymphoblastic leukemia (ALL) [106]. Similarly, another study confirmed a role for VCP/p97 in glucocorticoidresistant leukemic cells [120]. Notably, a proteomic approach indicated that VCP/p97 was the most abundant protein involved in exosome generation and secretion in T-cell leukemia Jurkat cells; indeed, VCP/p97 inhibition prevented tumor exosome secretion, thus highlighting a potential novel mechanism of VCP/p97 in tumorigenesis [107].…”

Section: Vcp/p97 In Hematological Cancersmentioning

confidence: 87%

Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer

Costantini

Capone

Polo

et al. 2021

IJMS

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Valosin-containing protein (VCP)/p97, a member of the AAA+ ATPase family, is a molecular chaperone recruited to the endoplasmic reticulum (ER) membrane by binding to membrane adapters (nuclear protein localization protein 4 (NPL4), p47 and ubiquitin regulatory X (UBX) domain-containing protein 1 (UBXD1)), where it is involved in ER-associated protein degradation (ERAD). However, VCP/p97 interacts with many cofactors to participate in different cellular processes that are critical for cancer cell survival and aggressiveness. Indeed, VCP/p97 is reported to be overexpressed in many cancer types and is considered a potential cancer biomarker and therapeutic target. This review summarizes the role of VCP/p97 in different cancers and the advances in the discovery of small-molecule inhibitors with therapeutic potential, focusing on the challenges associated with cancer-related VCP mutations in the mechanisms of resistance to inhibitors.

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Section: Vcp/p97 In Hematological Cancersmentioning

confidence: 87%

Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer

Costantini

Capone

Polo

et al. 2021

IJMS

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“…In recent years, the effectiveness of Bortezomib was also tested for the treatment of acute lymphoblastic leukemia. It was shown that bortezomib can sensitize in-vitro GC-resistant childhood B-cell precursor leukemia cell lines, MHH-cALL-2 and MHH-cALL-3, to prednisolone-induced cell death via inhibiting the proteasome (Junk et al 2015). The use of proteasome inhibitors to sensitize GC-resistant ALL cells was supported by detecting that high expression of valosin-containing protein (VCP), a member of the ubiquitin proteasome degradation system (UPS), is associated with poor response to prednisolone treatment in childhood ALL patients (Lauten et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Differential network analysis and protein-protein interaction study reveals active protein modules in glucocorticoid resistance for infant acute lymphoblastic leukemia

Mousavian

Nowzari-Dalini

Rahmatallah

et al. 2019

Mol Med

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Background Acute lymphoblastic leukemia (ALL) is the most common type of cancer diagnosed in children and Glucocorticoids (GCs) form an essential component of the standard chemotherapy in most treatment regimens. The category of infant ALL patients carrying a translocation involving the mixed lineage leukemia (MLL) gene (gene KMT2A) is characterized by resistance to GCs and poor clinical outcome. Although some studies examined GC-resistance in infant ALL patients, the understanding of this phenomenon remains limited and impede the efforts to improve prognosis. Methods This study integrates differential co-expression (DC) and protein-protein interaction (PPI) networks to find active protein modules associated with GC-resistance in MLL-rearranged infant ALL patients. A network was constructed by linking differentially co-expressed gene pairs between GC-resistance and GC-sensitive samples and later integrated with PPI networks by keeping the links that are also present in the PPI network. The resulting network was decomposed into two sub-networks, specific to each phenotype. Finally, both sub-networks were clustered into modules using weighted gene co-expression network analysis (WGCNA) and further analyzed with functional enrichment analysis. Results Through the integration of DC analysis and PPI network, four protein modules were found active under the GC-resistance phenotype but not under the GC-sensitive. Functional enrichment analysis revealed that these modules are related to proteasome, electron transport chain, tRNA-aminoacyl biosynthesis, and peroxisome signaling pathways. These findings are in accordance with previous findings related to GC-resistance in other hematological malignancies such as pediatric ALL. Conclusions Differential co-expression analysis is a promising approach to incorporate the dynamic context of gene expression profiles into the well-documented protein interaction networks. The approach allows the detection of relevant protein modules that are highly enriched with DC gene pairs. Functional enrichment analysis of detected protein modules generates new biological hypotheses and may help in explaining the GC-resistance in MLL-rearranged infant ALL patients. Electronic supplementary material The online version of this article (10.1186/s10020-019-0106-1) contains supplementary material, which is available to authorized users.

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“…Bortezomib (BTZ) is a small molecule proteasome inhibitor that mainly inhibits 26S proteasome, thereby inhibiting many processes involved in cell cycle regulation, apoptosis, cell adhesion, angiogenesis, and chemical resistance [165]. Studies have shown that BTZ can increase the sensitivity of cancer cells to chemotherapeutic drugs and effectively reduce the resistance of cancer cells to chemotherapy [166]. BTZ has a significant cytotoxic effect on NSCLC.…”

Section: Advances In the Combination Of Cell Cycle Regulation And Che...mentioning

confidence: 99%

The Influence of Cell Cycle Regulation on Chemotherapy

Sun

Yang

Ma³

et al. 2021

IJMS

147

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Cell cycle regulation is orchestrated by a complex network of interactions between proteins, enzymes, cytokines, and cell cycle signaling pathways, and is vital for cell proliferation, growth, and repair. The occurrence, development, and metastasis of tumors are closely related to the cell cycle. Cell cycle regulation can be synergistic with chemotherapy in two aspects: inhibition or promotion. The sensitivity of tumor cells to chemotherapeutic drugs can be improved with the cooperation of cell cycle regulation strategies. This review presented the mechanism of the commonly used chemotherapeutic drugs and the effect of the cell cycle on tumorigenesis and development, and the interaction between chemotherapy and cell cycle regulation in cancer treatment was briefly introduced. The current collaborative strategies of chemotherapy and cell cycle regulation are discussed in detail. Finally, we outline the challenges and perspectives about the improvement of combination strategies for cancer therapy.

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Bortezomib Treatment can Overcome Glucocorticoid Resistance in Childhood B-cell Precursor Acute Lymphoblastic Leukemia Cell Lines

Abstract: The proteasome inhibitor bortezomib seems to sensitize gc-resistant childhood ALL cells for prednisolone-induced cell death.

Cited by 9 publications

References 34 publications

Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer

Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer

Differential network analysis and protein-protein interaction study reveals active protein modules in glucocorticoid resistance for infant acute lymphoblastic leukemia

The Influence of Cell Cycle Regulation on Chemotherapy

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