Nuclear translocation of dihydrofolate reductase is not a pre-requisite for DNA damage induced apoptosis

Yuan, Tingting; Huang, Ying; Zhou, Chenyu; Yu, Yun; Wang, Li‐Shun; Zhuang, Huisheng; Chen, Guoqiang

doi:10.1007/s10495-009-0343-9

Cited by 6 publications

(4 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, the folate metabolism enzyme, methylene-THF dehydrogenase, cyclohydrolase, and formyl-THF synthetase 1, has recently been shown to associate with chromatin and regulate gene expression ( 27 ). However, similar studies have yet to be completed for nuclear DHFR ( 28 ). Thus, our findings that loss of DHFR via siRNA targeting or pyrimethamine treatment dampens STAT3 transcriptional activity without significantly reducing STAT3 tyrosine phosphorylation ( Figs.…”

Section: Discussionmentioning

confidence: 99%

The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase

Heppler

Attarha

Persaud

et al. 2022

Journal of Biological Chemistry

View full text Add to dashboard Cite

Cancer is often characterized by aberrant gene expression patterns caused by the inappropriate activation of transcription factors. Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional regulator of many protumorigenic processes and is persistently activated in many types of human cancer. However, like many transcription factors, STAT3 has proven difficult to target clinically. To address this unmet clinical need, we previously developed a cell-based assay of STAT3 transcriptional activity and performed an unbiased and high-throughput screen of small molecules known to be biologically active in humans. We identified the antimicrobial drug pyrimethamine as a novel and specific inhibitor of STAT3 transcriptional activity. Here, we show that pyrimethamine does not significantly affect STAT3 phosphorylation, nuclear translocation, or DNA binding at concentrations sufficient to inhibit STAT3 transcriptional activity, suggesting a potentially novel mechanism of inhibition. To identify the direct molecular target of pyrimethamine and further elucidate the mechanism of action, we used a new quantitative proteome profiling approach called proteome integral solubility alteration coupled with a metabolomic analysis. We identified human dihydrofolate reductase as a target of pyrimethamine and demonstrated that the STAT3-inhibitory effects of pyrimethamine are the result of a deficiency in reduced folate downstream of dihydrofolate reductase inhibition, implicating folate metabolism in the regulation of STAT3 transcriptional activity. This study reveals a previously unknown regulatory node of the STAT3 pathway that may be important for the development of novel strategies to treat STAT3-driven cancers.

show abstract

Section: Discussionmentioning

confidence: 99%

The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase

Heppler

Attarha

Persaud

et al. 2022

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…More intriguingly, further analysis showed that the ANP32B caspase-3 cleavage fragment might have important roles in apoptotic regulation (data not shown). In addition, hnRNPK was also found to decrease via proteasome degradation during apoptosis, and its knockdown also contributed to apoptosis induction [50]. In addition, we found that dihydrofolate reductase (DHFR) is translocated from the cytosol to the nucleus during the apoptosis [51].…”

Section: Chemical Compound-induced Apoptosismentioning

confidence: 83%

Current advances in the application of proteomics in apoptosis research

Wang

Chen

2011

Sci. China Life Sci.

View full text Add to dashboard Cite

Apoptosis, or programmed cell death, is a complex, genetically-determined process involved in the development and maintenance of homeostasis in multicellular organisms. Dysregulation of apoptosis has been implicated in a number of diseases, including cancer and autoimmune disease. Thus, the investigation of apoptotic regulation has evoked considerable interest. Many apoptotic proteins have been shown to be post-translationally modulated, such as by protein cleavage, translocation, protein-protein interaction, and various post-translational modifications, which fall precisely within the range of proteomic analysis. Recently, contemporary proteomic technologies have achieved significant advances and have accelerated research in functional and chemical proteomics, which have been applied to the field of apoptosis research and have the potential to be a driving force for the field. This review highlights some of the major achievements in the application of proteomics in apoptosis research and discusses new directions and challenges for the near future.

show abstract

“…The latter was more pronounced in cell death induced by DNA-damaging agents than endoplasmic reticulum stressors. It was also found that the addition of methotrexate almost completely blocked the nuclear translocation of DHFR protein while it failed to impinge on the apoptosis induction [59] . Moreover, using leukemic cell apoptosis induced by NSC606985 and other chemotherapeutic agents as a model, we confirmed that PU.1 [60] (one of the key regulators of hematopoietic cell development) and leukemia-associated fusion protein AML1-ETO [61] are direct substrates of the apoptosis executioner caspase-3 and their target sites for caspase-3 cleavage have been identified by site-directed mutagenesis.…”

Section: Discoveries About Cell Apoptosis Induction Based On Small Momentioning

confidence: 96%

Active compounds-based discoveries about the differentiation and apoptosis of leukemic cells

2009

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic malignancies which are characterized by the blockage of hematopoietic cell differentiation with uncontrolled proliferation and/or impaired apoptosis. Over the past 20 years, there has been tremendous progress in the biological, molecular, and cytogenetic aspects of the disease, accompanied by significant advancements in the treatment of AML patients. For example, all-trans retinoic acid (ATRA) and arsenic trioxide (As 2 O 3 ) have been used clinically for effective treatments of patients with acute promyelocytic leukemia (APL, a unique subtype of AML) through differentiation and/or apoptosis induction. More intriguingly, these active compounds-based chemical biological studies greatly accelerated our understanding on leukemogenesis and targeted therapy of AML patients. Based on some recent findings mainly from our group, this review attempts to summarize the related advances from Chinese researchers. chemical biology, leukemia, cell differentiation, apoptosis Acute myeloid leukemia (AML), a heterogeneous group of hematopoietic malignancies, occurs frequently in adults. Remarkable advances in the biological, molecular and cytogenetic aspects of this disease have been made over the past 20 years. It is well-established that specific cytogenetic alterations, particularly chromosomal translocations that generate abnormal oncogenic fusion proteins, such as t(15;17) yielding PML-RARα (promyelocytic leukemia-retinoic acid receptor-alpha) and t(8;21) yielding AML1-ETO (acute myeloid leukemia 1-eight twenty-one), cause the blockage of hematopoietic cell differentiation at a certain stage, accompanied by uncontrolled proliferation and/or impaired apoptosis. On the other hand, the past decades are also marked by great advances in the treatment of AML patients. One typical example is the discovery that all-trans retinoic acid (ATRA) and arsenic trioxide (As 2 O 3 ) could effectively treat patients with acute promyelocytic leukemia (APL, also known as M3-type AML) through the induction of differentiation and/or apoptosis. Due to the relative convenience of acquiring leukemia samples and the ease of the evaluation of therapeutic effects, chemical biological methodologies that use specific, active small molecules (such as ATRA and As 2 O 3 ) as probes to investigate mechanisms of basic cellular activities greatly accelerated our understanding of leukemogenesis and targeted therapy of AML patients [1] . Based on some recent findings primarily from our group, this review attempts to summarize the related advances from Chinese researchers.

show abstract

Nuclear translocation of dihydrofolate reductase is not a pre-requisite for DNA damage induced apoptosis

Cited by 6 publications

References 40 publications

The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase

The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase

Current advances in the application of proteomics in apoptosis research

Active compounds-based discoveries about the differentiation and apoptosis of leukemic cells

Contact Info

Product

Resources

About