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  • Proceedings of the National Academy of Sciences  (5)
  • 1
    Online Resource
    Online Resource
    Transient induction of telomerase expression mediates senescence and reduces tumorigenesis in primary fibroblasts
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 38 ( 2019-09-17), p. 18983-18993
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 38 ( 2019-09-17), p. 18983-18993
    Abstract: Telomerase is an enzymatic ribonucleoprotein complex that acts as a reverse transcriptase in the elongation of telomeres. Telomerase activity is well documented in embryonic stem cells and the vast majority of tumor cells, but its role in somatic cells remains to be understood. Here, we report an unexpected function of telomerase during cellular senescence and tumorigenesis. We crossed Tert heterozygous knockout mice ( mTert +/− ) for 26 generations, during which time there was progressive shortening of telomeres, and obtained primary skin fibroblasts from mTert +/+ and mTert −/− progeny of the 26th cross. As a consequence of insufficient telomerase activities in prior generations, both mTert +/+ and mTert −/− fibroblasts showed comparable and extremely short telomere length. However, mTert −/− cells approached cellular senescence faster and exhibited a significantly higher rate of malignant transformation than mTert +/+ cells. Furthermore, an evident up-regulation of telomerase reverse-transcriptase (TERT) expression was detected in mTert +/+ cells at the presenescence stage. Moreover, removal or down-regulation of TERT expression in mTert +/+ and human primary fibroblast cells via CRISPR/Cas9 or shRNA recapitulated mTert −/− phenotypes of accelerated senescence and transformation, and overexpression of TERT in mTert −/− cells rescued these phenotypes. Taking these data together, this study suggests that TERT has a previously underappreciated, protective role in buffering senescence stresses due to short, dysfunctional telomeres, and preventing malignant transformation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1907199116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Off-tumor targets compromise antiangiogenic drug sensitivity by inducing kidney erythropoietin production
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 45 ( 2017-11-07)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 45 ( 2017-11-07)
    Abstract: Anti-VEGF drugs are commonly used for treatment of a variety of cancers in human patients, and they often develop resistance. The mechanisms underlying anti-VEGF resistance in human cancer patients are largely unknown. Here, we show that in mouse tumor models and in human cancer patients, the anti-VEGF drug-induced kidney hypoxia augments circulating levels of erythropoietin (EPO). Gain-of-function studies show that EPO protects tumor vessels from anti-VEGF treatment and compromises its antitumor effects. Loss of function by blocking EPO function using a pharmacological approach markedly increases antitumor activity of anti-VEGF drugs through inhibition of tumor angiogenesis. Similarly, genetic loss-of-function data shows that deletion of EpoR in nonerythroid cells significantly increases antiangiogenic and antitumor effects of anti-VEGF therapy. Finally, in a relatively large cohort study, we show that treatment of human colorectal cancer patients with bevacizumab augments circulating EPO levels. These findings uncover a mechanism of desensitizing antiangiogenic and anticancer effects by kidney-produced EPO. Our work presents conceptual advances of our understanding of mechanisms underlying antiangiogenic drug resistance.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1703431114
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Maintenance of antiangiogenic and antitumor effects by orally active low-dose capecitabine for long-term cancer therapy
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 26 ( 2017-06-27)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 26 ( 2017-06-27)
    Abstract: Long-term uninterrupted therapy is essential for maximizing clinical benefits of antiangiogenic drugs (AADs) in cancer patients. Unfortunately, nearly all clinically available AADs are delivered to cancer patients using disrupted regimens. We aim to develop lifetime, nontoxic, effective, orally active, and low-cost antiangiogenic and antitumor drugs for treatment of cancer patients. Here we report our findings of long-term maintenance therapy with orally active, nontoxic, low cost antiangiogenic chemotherapeutics for effective cancer treatment. In a sequential treatment regimen, robust antiangiogenic effects in tumors were achieved with an anti-VEGF drug, followed by a low-dose chemotherapy. The nontoxic, low dose of the orally active prodrug capecitabine was able to sustain the anti-VEGF–induced vessel regression for long periods. In another experimental setting, maintenance of low-dose capecitabine produced greater antiangiogenic and antitumor effects after AAD plus chemotherapy. No obvious adverse effects were developed after more than 2-mo of consecutive treatment with a low dose of capecitabine. Together, our findings provide a rationalized concept of effective cancer therapy by long-term maintenance of AAD-triggered antiangiogenic effects with orally active, nontoxic, low-cost, clinically available chemotherapeutics.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1705066114
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    G9a coordinates with the RPA complex to promote DNA damage repair and cell survival
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 30 ( 2017-07-25)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 30 ( 2017-07-25)
    Abstract: Histone methyltransferase G9a has critical roles in promoting cancer-cell growth and gene suppression, but whether it is also associated with the DNA damage response is rarely studied. Here, we report that loss of G9a impairs DNA damage repair and enhances the sensitivity of cancer cells to radiation and chemotherapeutics. In response to DNA double-strand breaks (DSBs), G9a is phosphorylated at serine 211 by casein kinase 2 (CK2) and recruited to chromatin. The chromatin-enriched G9a can then directly interact with replication protein A (RPA) and promote loading of the RPA and Rad51 recombinase to DSBs. This mechanism facilitates homologous recombination (HR) and cell survival. We confirmed the interaction between RPA and G9a to be critical for RPA foci formation and HR upon DNA damage. Collectively, our findings demonstrate a regulatory pathway based on CK2–G9a–RPA that permits HR in cancer cells and provide further rationale for the use of G9a inhibitors as a cancer therapeutic.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1700694114
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 5
    Online Resource
    Online Resource
    Pharmacological disruption of the Notch transcription factor complex
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 28 ( 2020-07-14), p. 16292-16301
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 28 ( 2020-07-14), p. 16292-16301
    Abstract: Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1922606117
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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