CCN2 induces cellular senescence in fibroblasts

Jun, Joon-II; Lau, Lester F.

doi:10.1007/s12079-016-0359-1

Cited by 53 publications

(51 citation statements)

References 43 publications

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“…The expression of CDKN2B was significantly enhanced in tumors from mice treated with ETC-159 alone and further increased in tumors treated with the combination containing olaparib ( Figure 6C). In addition, expression of the senescence markers IL32 and CCN2 and protein levels of p21 (53)(54)(55) were also higher in the tumors from the ETC-159 and olaparib combination group compared to the tumors treated with ETC-159 or olaparib alone (Figures 6C-D). Loss of LMNB1 (lamin B1) is also associated with senescence (56, 57) and we observed a marked reduction in its expression in the tumors treated with ETC-159 either alone or in combination with olaparib ( Figure 6E).…”

Section: Olaparib and Etc--159 Combination Enhances Senescencementioning

confidence: 92%

WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

Kaur

Sepramaniam

Lim

et al. 2020

Preprint

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Wnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have 30 proven effective in Wnt-addicted preclinical cancer models and are in clinical trials. In a survey for potential combination therapies, we found that Wnt inhibition synergizes with the PARP inhibitor olaparib in Wnt-addicted cancers. Mechanistically, we find that multiple genes in the homologous recombination and Fanconi anemia repair pathways, including BRCA1, FANCD2, and RAD51 are dependent on Wnt/β-catenin signaling in Wnt-high cancers, and treatment with a PORCN inhibitor creates a BRCA-like state. This coherent regulation of DNA repair genes occurs via a Wnt/β-catenin/MYBL2 axis. Importantly, this pathway also functions in intestinal crypts, where high expression of BRCA and Fanconi anemia genes is seen in intestinal stem cells, with further upregulation in Wnt high APC min mutant polyps. Our findings suggest a general paradigm that Wnt/β-40 catenin signaling enhances DNA repair in stem cells and cancers to maintain genomic integrity. Conversely, interventions that block Wnt signaling may sensitize cancers to radiation and other DNA damaging agents. 610

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Section: Olaparib and Etc--159 Combination Enhances Senescencementioning

confidence: 92%

WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

Kaur

Sepramaniam

Lim

et al. 2020

Preprint

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“…3.2 | CCN2 increases ABCG2 expression via the α6β1 integrin receptor in human osteosarcoma cells CCN2 is capable of binding various growth factors or integrins and modifying their activity in certain carcinoma cells (Jun & Lau, 2017;Yang et al, 2016;Zeng et al, 2017). The most researched CCNbinding receptors are the integrins αvβ3, αvβ5, α5β1, and α6β1 (Lau, 2016).…”

Section: Ccn2 Enhances Abcg2 Expression and Increases Osteosarcoma mentioning

confidence: 99%

CCN2 promotes drug resistance in osteosarcoma by enhancing ABCG2 expression

Tsai

Chang

Tsai

et al. 2018

Journal Cellular Physiology

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In recent years, osteosarcoma survival rates have failed to improve significantly with conventional treatment modalities because of the development of chemotherapeutic resistance. The human breast cancer resistance protein/ATP binding cassette subfamily G member 2 (BCRP/ABCG2), a member of the ATP‐binding cassette family, uses ATP hydrolysis to expel xenobiotics and chemotherapeutics from cells. CCN family member 2 (CCN2) is a secreted protein that modulates the biological function of cancer cells, enhanced ABCG2 protein expression and activation in this study via the α6β1 integrin receptor and increased osteosarcoma cell viability. CCN2 treatment downregulated miR‐519d expression, which promoted ABCG2 expression. In a mouse xenograft model, knockdown of CCN2 expression increased the therapeutic effect of doxorubicin, which was reversed by ABCG2 overexpression. Our data show that CCN2 increases ABCG2 expression and promotes drug resistance through the α6β1 integrin receptor, whereas CCN2 downregulates miR‐519d. CCN2 inhibition may represent a new therapeutic concept in osteosarcoma.

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“…Upregulation of Ccn1 was vitally important to prevent excessive fibrosis. More recently, the same authors demonstrated that topical application of another Ccn family member, Ccn2, similarly actuates senescence and reduces fibrosis in cutaneous murine wounds (Jun and Lau, 2017).…”

Section: Senescence In Normal Tissue Repairmentioning

confidence: 95%

Senescence in Wound Repair: Emerging Strategies to Target Chronic Healing Wounds

Wilkinson

Hardman

2020

Front. Cell Dev. Biol.

105

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Cellular senescence is a fundamental stress response that restrains tumour formation. Yet, senescence cells are also present in non-cancerous states, accumulating exponentially with chronological age and contributing to age-and diabetes-related cellular dysfunction. The identification of hypersecretory and phagocytic behaviours in cells that were once believed to be non-functional has led to a recent explosion of senescence research. Here we discuss the profound, and often opposing, roles identified for short-lived vs. chronic tissue senescence. Transiently induced senescence is required for development, regeneration and acute wound repair, while chronic senescence is widely implicated in tissue pathology. We recently demonstrated that sustained senescence contributes to impaired diabetic healing via the CXCR2 receptor, which when blocked promotes repair. Further studies have highlighted the beneficial effects of targeting a range of senescence-linked processes to fight disease. Collectively, these findings hold promise for developing clinically viable strategies to tackle senescence in chronic wounds and other cutaneous pathologies.

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CCN2 induces cellular senescence in fibroblasts

Cited by 53 publications

References 43 publications

WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

CCN2 promotes drug resistance in osteosarcoma by enhancing ABCG2 expression

Senescence in Wound Repair: Emerging Strategies to Target Chronic Healing Wounds

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