Cellular stress causes cancer cell chemoresistance
Postgenomic technologies reveal new mechanism of stress-induced chemoresistance

Date:
June 10, 2020
Source:
University of Vienna
Summary:
Resistance of cancer cells against therapeutic agents is a major
cause of treatment failure, especially in recurrent diseases. An
international team has now identified a novel mechanism of
chemoresistance.



FULL STORY ========================================================================== There is a broad range of mechanisms associated with chemoresistance,
many of which to date are only poorly understood. The so-called cellular
stress response -- a set of genetic programmes that enable the cells to
survive under stressful conditions -- plays a key role in the development
of numerous diseases and in chemoresistance. A better understanding of
the cellular stress response pathways is therefore urgently required to
develop new therapeutic concepts to overcome chemoresistance. "In this
context, we employed comprehensive analytical approaches to gain deep and molecular insight into the Unfolded Protein Response, a cellular stress reaction induced by unfolded proteins," says Robert Ahrends, group leader
at the Department of Analytical Chemistry of the Faculty of Chemistry.


========================================================================== Unfolded proteins cause stress and disease The Unfolded Protein Response
(UPR) contributes to cancer development and progression and plays an
important role in diseases such as diabetes and neurodegenerative
disorders. For their study of the UPR's molecular biological
characteristics, the researchers applied state-to-art analytical tools
in the context of a multiomics approach, combining large datasets from genetics, proteomics and metabolomics. This allowed them to define the
Unfolded Protein Response regulon, a comprehensive list of genes that
are activated to promote cell survival under stress.

"Besides the previously known factors, we identified to our surprise
numerous genes that have not previously been implicated in stress response pathways," explain the researchers, "and many of them have key functions
in cancer development and cellular metabolism." Changes in 1C metabolism Changes in cellular metabolism are characteristic of many cancer types
and promote a rapid tumour growth, as Nobel Prize winner Otto Warburg demonstrated already in the 1930s in his ground-breaking work. In their
study, the researchers discovered stress-mediated genetic regulation
of enzymes involved in one-carbon (1C) metabolism which relies on the
vitamin folate as a cofactor.

Concomitant to the metabolic re-wiring, the stressed cells became fully resistant against chemotherapeutic agents, which target this specific
metabolic pathway. This includes Methotrexate, a drug commonly employed
in the treatment of cancer and rheumatic diseases. Detailed biochemical
and genetic investigations revealed that resistance is driven by a
previously unrecognized mechanism. According to the study authors,
its precise molecular characterisation might lead to novel therapeutic
concepts aimed at overcoming chemoresistance in cancer therapy.


========================================================================== Story Source: Materials provided by University_of_Vienna. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Stefan Reich, Chi D. L. Nguyen, Canan Has, Sascha Steltgens,
Himanshu
Soni, Cristina Coman, Moritz Freyberg, Anna Bichler, Nicole Seifert,
Dominik Conrad, Christiane B. Knobbe-Thomsen, Bjo"rn Tews, Grischa
Toedt, Robert Ahrends, Jan Medenbach. A multi-omics analysis
reveals the unfolded protein response regulon and stress-induced
resistance to folate-based antimetabolites. Nature Communications,
2020; 11 (1) DOI: 10.1038/s41467-020-16747-y ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200610112049.htm

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