XPO1 is a critical player for bortezomib resistance in multiple myeloma: A quantitative proteomic approach

Chanukuppa, Venkatesh; Paul, Debasish; Taunk, Khushman; Chatterjee, Tathagata; Sharma, Sanjeevan; Kumar, Saravanan; Santra, Manas Kumar; Rapole, Srikanth

doi:10.1016/j.jprot.2019.103504

Cited by 34 publications

(37 citation statements)

References 53 publications

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“…349 Moreover, bortezomib resistance may occur within an average of 1 year, especially for solid tumors. [350][351][352] The resistance mechanism includes an enhanced aggresome-autophagy pathway, increased expression of proinflammatory macrophages, alterations in apoptotic signaling and decreased ER stress response. 353,354 Another approved PI for relapsed or refractory MM is carfilzomib (PR-171; Kyprolis; Onyx Pharmaceutical), a second-inclass PI (Fig.…”

Section: Nanog Ubiquitinationmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

419

308

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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Section: Nanog Ubiquitinationmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

419

308

View full text Add to dashboard Cite

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“…Another gene identified in this study was NUP50 . NUP50 can form a protein cluster with XPO1 , which is inhibited by bortezomib, showing inhibiting activity in multiple myeloma ( 24 ). PTTG1 has also been associated with the occurrence of tumors.…”

Section: Discussionmentioning

confidence: 99%

Identification of Subtype-Specific Metastasis-Related Genetic Signatures in Sarcoma

Gao

Niu

et al. 2020

Front. Oncol.

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Background: Sarcomas are heterogeneous rare malignancies constituting approximately 1% of all solid cancers in adults and including more than 70 histological and molecular subtypes with different pathological and clinical development characteristics. Method: We identified prognostic biomarkers of sarcomas by integrating clinical information and RNA-seq data from TCGA and GEO databases. In addition, results obtained from cell cycle, cell migration, and invasion assays were used to assess the capacity for Tanespimycin to inhibit the proliferation and metastasis of sarcoma. Results: Sarcoma samples ( N = 536) were divided into four pathological subtypes including DL (dedifferentiated liposarcoma), LMS (leiomyosarcoma), UPS (undifferentiated pleomorphic sarcomas), and MFS (myxofibrosarcoma). RNA-seq expression profile data from the TCGA dataset were used to analyze differentially expressed genes (DEGs) within metastatic and non-metastatic samples of these four sarcoma pathological subtypes with DEGs defined as metastatic-related signatures (MRS). Prognostic analysis of MRS identified a group of genes significantly associated with prognosis in three pathological subtypes: DL, LMS, and UPS. ISG15, NUP50, PTTG1, SERPINE1 , and TSR1 were found to be more likely associated with adverse prognosis. We also identified Tanespimycin as a drug exerting inhibitory effects on metastatic LMS subtype and therefore can serve a potential treatment for this type of sarcoma. Conclusions: These results provide new insights into the pathogenesis, diagnosis, treatment, and prognosis of sarcomas and provide new directions for further study of sarcoma.

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“…Proteasome inhibition in colorectal cancer cells induces CRM1-dependent nuclear export of ubiquitinated proteins, and inhibition of CRM1 prevents this export, leading to cell cycle arrest and apoptosis [24]. In addition, CRM1 inhibition re-sensitizes chemo-resistant myeloma cells to proteasome inhibition [34]. Inhibiting these inter-dependent pathways .…”

Section: Discussionmentioning

confidence: 99%

A cross-species drug discovery pipeline to identify and validate new treatments for osteosarcoma

Somarelli

Rupprecht

Altunel

et al. 2020

Preprint

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Purpose: Osteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease. Experimental design: To overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline. Results: Coupling in vitro high-throughput drug screens on low-passage and established cell lines with in vivo validation in patient-derived xenografts we identify the proteasome and CRM1 nuclear export pathways as therapeutic sensitivities in osteosarcoma, with dual inhibition of these pathways inducing synergistic cytotoxicity. Conclusions: These collective efforts provide an experimental framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities.

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XPO1 is a critical player for bortezomib resistance in multiple myeloma: A quantitative proteomic approach

Cited by 34 publications

References 53 publications

The role of ubiquitination in tumorigenesis and targeted drug discovery

The role of ubiquitination in tumorigenesis and targeted drug discovery

Identification of Subtype-Specific Metastasis-Related Genetic Signatures in Sarcoma

A cross-species drug discovery pipeline to identify and validate new treatments for osteosarcoma

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