Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Resistance development to one chemotherapeutic reagent leads frequently to acquired tolerance to other compounds, limiting the therapeutic options for cancer treatment. Herein, we find that overexpression of Rac1 is associated with multi-drug resistance to the neoadjuvant chemotherapy (NAC). Mechanistically, Rac1 activates aldolase A and ERK signaling which up-regulates glycolysis and especially the non-oxidative pentose phosphate pathway (PPP). This leads to increased nucleotides metabolism which protects breast cancer cells from chemotherapeutic-induced DNA damage. To translate this finding, we develop endosomal pH-responsive nanoparticles (NPs) which deliver Rac1-targeting siRNA together with cisplatin and effectively reverses NAC-chemoresistance in PDXs from NAC-resistant breast cancer patients. Altogether, our findings demonstrate that targeting Rac1 is a potential strategy to overcome acquired chemoresistance in breast cancer.

Abstract

Acquired resistance to chemotherapy can lead to multi-drug resistance and poor prognosis in cancer. Here, the authors show that Rac1 increases glycolysis and non-oxidative pentose phosphate pathway activity leading to neoadjuvant chemotherapy (NAC) resistance, thus its inhibition sensitizes resistant breast cancer PDXs to NAC.

Related collections

Most cited references 37

Record: found
Abstract: found
Article: not found

Knocking down barriers: advances in siRNA delivery

Kathryn Whitehead, Róbert Miklós Langer, Daniel Anderson (2009)

Key Points RNA interference (RNAi) is a fundamental pathway in eukaryotic cells by which sequence-specific small interfering RNA (siRNA) is able to silence genes through the destruction of complementary mRNA. RNAi is an important therapeutic tool that can be used to silence aberrant endogenous genes or to knockdown genes essential to the proliferation of infectious organisms. Delivery remains the central challenge to the therapeutic application of RNAi technology. Before siRNA can take effect in the cytoplasm of a target cell, it must be transported through the body to the target site without undergoing clearance or degradation. Currently, the most effective synthetic, non-viral delivery agents of siRNA are lipids, lipid-like materials and polymers. Various cationic agents including stable nucleic acid–lipid particles, lipidoids, cyclodextrin polymers and polyethyleneimine polymers have been used to achieve the successful systemic delivery of siRNA in mammals without inducing significant toxicity. Direct conjugation of delivery agents to siRNA can facilitate delivery. For example, cholesterol-modified siRNA enables targeting to the liver. RNAi therapeutics have progressed to the clinic, where studies are being conducted to determine siRNA efficacy in treating several diseases, including age-related macular degeneration and respiratory syncytial virus. Moving forward, it will be important to pay close attention to the potential nonspecific immunostimulatory effects of siRNA. Modifications to siRNA can be used to minimize stimulation of the immune system, and an increased emphasis must be placed on performing proper controls to ensure that therapeutic effects are sequence-specific.

0 comments Cited 766 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

RNAi-mediated gene silencing in non-human primates.

Tracy Zimmermann, Amy Lee, Akin Akinc … (2006)

The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.

0 comments Cited 314 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

DNA-damaging agents in cancer chemotherapy: serendipity and chemical biology.

Kahlin Cheung-Ong, Guri Giaever, Corey Nislow (2013)

DNA-damaging agents have a long history of use in cancer chemotherapy. The full extent of their cellular mechanisms, which is essential to balance efficacy and toxicity, is often unclear. In addition, the use of many anticancer drugs is limited by dose-limiting toxicities as well as the development of drug resistance. Novel anticancer compounds are continually being developed in the hopes of addressing these limitations; however, it is essential to be able to evaluate these compounds for their mechanisms of action. This review covers the current DNA-damaging agents used in the clinic, discusses their limitations, and describes the use of chemical genomics to uncover new information about the DNA damage response network and to evaluate novel DNA-damaging compounds. Copyright © 2013 Elsevier Ltd. All rights reserved.

0 comments Cited 219 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Herui Yao: yaoherui@163.com

Hai Hu: huhai@mail.sysu.edu.cn

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 19 March 2020

Publication date PMC-release: 19 March 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 1456

Affiliations

[1 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Department of Oncology, Sun Yat-Sen Memorial Hospital, , Sun Yat-Sen University, ; 510120 Guangzhou, People’s Republic of China

[2 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, , Sun Yat-Sen University, ; 510120 Guangzhou, People’s Republic of China

[3 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, , Sun Yat-Sen University, ; 510120 Guangzhou, China

[4 ]ISNI 000000041936754X, GRID grid.38142.3c, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center and Department of Medicine, , Harvard Medical School, ; Boston, MA 02115 USA

Author information

Yandan Yao http://orcid.org/0000-0003-3151-9019

Gerburg M. Wulf http://orcid.org/0000-0001-7868-6231

Erwei Song http://orcid.org/0000-0002-5400-9049

Article

Publisher ID: 15308

DOI: 10.1038/s41467-020-15308-7

PMC ID: 7081201

PubMed ID: 32193458

SO-VID: 1dae37ac-8afa-46df-a390-587d9ef6d4a2

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 13 March 2019

Date accepted : 27 February 2020

Funding

Funded by: Natural Science Foundation of China (81672738, 81730077 to H.H.)

Custom metadata

ScienceOpen disciplines: Uncategorized

Keywords: breast cancer,cancer metabolism,cancer therapy

Data availability:

ScienceOpen disciplines: Uncategorized

Keywords: breast cancer, cancer metabolism, cancer therapy

Comments

Comment on this article

scite_

156

Smart Citations

156

Citing PublicationsSupportingMentioningContrasting

View Citations

See how this article has been cited at scite.ai

scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.