Role of hypoxia in cancer therapy by regulating the tumor microenvironment

Jing, Xinming; Yang, Fengming; Shao, Chao‐Peng; Wei, Ke; Xie, Mengyan; Shen, Hua; Shu, Yongqian

doi:10.1186/s12943-019-1089-9

Cited by 1,315 publications

(1,087 citation statements)

References 128 publications

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“…462 The molecular mechanisms of anti-cancer drug resistance are also associated with tumor metabolism, the TME and CSCs, such as increasing drug metabolism and degradation of drug target proteins, enhance the tolerability of stressful TME conditions, and enhance the DNA damage response and antiapoptotic mechanisms of CSCs. 461,[463][464][465][466] Thus, to improve therapeutic effects, a multitargeted combination treatment is proposed for UPS inhibitors.…”

Section: Targeting E3 Enzymesmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

431

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: Targeting E3 Enzymesmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

431

308

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“…It was clearly shown that the hypoxia condition affects the gene expression 21 . Numerous studies have demonstrated that the hypoxia microenvironment in the solid tumor contributes to cancer development and progression 6,14,22,23 . The chromatin structure plays an important role in controlling gene expression 24 .…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of the hypoxia response regulatory elements in the accessible genome

Chen

2020

Preprint

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15Hypoxia is commonly observed in the solid tumor and contributes to the drug resistance in 16 cancer therapy. Deciphering the epigenetic feature under the hypoxia condition in the solid 17 tumor is critical for us to understand the tumorigenesis and design the precision therapy. 18Using the time series of ATAC-seq data under the hypoxia treatment from the epithelia cells, 19we identified the hypoxia response regulatory elements (HRREs) in the accessible genome. 20We found that these different HRREs have unique genomic features and are enriched with 21 different transcriptional factors (TFs). Our study provides insights into the chromatin 22 structure response to the hypoxia treatment and identifies useful genomic features for a better 23understanding of the hypoxia biology in the solid tumor. 24 25

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“…To be able to grow and spread, lymphoma cells must learn how to overcome stress-induced by hypoxia, acidosis, increased levels of reactive oxygen species (ROS), and lack of nutrients. Hypoxia belongs to widely recognized factors that in a very complex fashion facilitate tumor cell survival and chemoresistance in all types of malignant diseases [75]. Hypoxia-inducible factors (HIFs) play a central role in the string of adaptation phenotypic changes associated with hypoxia, both in lymphoma cells and non-malignant cells of the tumor microenvironment [76].…”

Section: Hypoxia-induced Changes and Metabolic Reprogrammingmentioning

confidence: 99%

Drug Resistance in Non-Hodgkin Lymphomas

Klener

Klánová

2020

IJMS

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Non-Hodgkin lymphomas (NHL) are lymphoid tumors that arise by a complex process of malignant transformation of mature lymphocytes during various stages of differentiation. The WHO classification of NHL recognizes more than 90 nosological units with peculiar pathophysiology and prognosis. Since the end of the 20th century, our increasing knowledge of the molecular biology of lymphoma subtypes led to the identification of novel druggable targets and subsequent testing and clinical approval of novel anti-lymphoma agents, which translated into significant improvement of patients’ outcome. Despite immense progress, our effort to control or even eradicate malignant lymphoma clones has been frequently hampered by the development of drug resistance with ensuing unmet medical need to cope with relapsed or treatment-refractory disease. A better understanding of the molecular mechanisms that underlie inherent or acquired drug resistance might lead to the design of more effective front-line treatment algorithms based on reliable predictive markers or personalized salvage therapy, tailored to overcome resistant clones, by targeting weak spots of lymphoma cells resistant to previous line(s) of therapy. This review focuses on the history and recent advances in our understanding of molecular mechanisms of resistance to genotoxic and targeted agents used in clinical practice for the therapy of NHL.

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Role of hypoxia in cancer therapy by regulating the tumor microenvironment

Cited by 1,315 publications

References 128 publications

The role of ubiquitination in tumorigenesis and targeted drug discovery

The role of ubiquitination in tumorigenesis and targeted drug discovery

Identification and characterization of the hypoxia response regulatory elements in the accessible genome

Drug Resistance in Non-Hodgkin Lymphomas

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