Collaborator of ARF (CARF) Regulates Proliferative Fate of Human Cells by Dose-dependent Regulation of DNA Damage Signaling

Cheung, Caroline; Singh, R. V.; Kalra, Rajkumar S.; Kaul, Sunil C.; Wadhwa, Renu

doi:10.1074/jbc.m114.547208

Cited by 38 publications

(57 citation statements)

References 26 publications

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“…As shown in several earlier reports [29][30][31][32][33][34] , CARF has been demonstrated as a dual regulator of cell proliferation fates. Its upregulation in replicative and stress induced senescence caused activation of p53-p21 WAF1 axis and growth arrest [29][30][31][32][33][34] . Knockdown of CARF caused ATR/Chk1-driven apoptosis 35 , and its super-high levels caused activation of EMT 37 through β-catenin function.…”

Section: Snol-a As a Natural Inhibitor Of Carfsupporting

confidence: 55%

“…Overexpression of CARF caused activation of DDR, promoting growth arrest and senescence via activated ATR-Chk1 pathway 34,41 . In light of this information, we examined ATR-Chk1 signaling axis in control and Snol-A treated SKOV-3 cells.…”

Section: Snol-a Caused Growth Arrest That Was Mediated By Upregulatiomentioning

confidence: 99%

“…Consistent to the earlier reports on tumor suppressor effect of CARF shRNA, Snol-A caused delay in tumor growth and inhibited lung metastasis suggested that it may be recruited as a natural inhibitor of CARF for cancer treatment. www.nature.com/scientificreports www.nature.com/scientificreports/ Discussion CARF (Collaborator of ARF) was shown to be an essential nuclear protein that possesses a dose dependent control on cell proliferation 29,34 . CARF-compromised cells showed caspase-dependent apoptosis 35 .…”

Section: Snol-a As a Natural Inhibitor Of Carfmentioning

confidence: 99%

“…CARF (Collaborator of ARF) is an essential cell-survival protein, originally identified as a novel binding partner of ARF (Alternative Reading Frame) 29,30 . It was shown to be an essential protein for cell survival 30,31 and plays a key role in control of cell proliferation fates through p53-HDM2-p21 WAF-1 and DNA damage signaling [32][33][34] . It was shown that whereas overexpression of CARF caused growth arrest in cancer cells, its super-expression leads to malignant transformation [33][34][35] .…”

mentioning

confidence: 99%

“…It was shown to be an essential protein for cell survival 30,31 and plays a key role in control of cell proliferation fates through p53-HDM2-p21 WAF-1 and DNA damage signaling [32][33][34] . It was shown that whereas overexpression of CARF caused growth arrest in cancer cells, its super-expression leads to malignant transformation [33][34][35] . CARF was shown to act by multiple mechanisms viz., its (i) direct interactions with proteins including ARF, p53, HDM2, (ii) transcriptional repression of HMD2 and p21 WAF131,36 and (iii) promote cancer cell invasion and malignant metastases via epithelial-mesenchymal transition (EMT) 37 .…”

mentioning

confidence: 99%

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Soyasapogenol-A targets CARF and results in suppression of tumor growth and metastasis in p53 compromised cancer cells

Omar

Kalra

Putri

et al. 2020

Sci Rep

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We screened some phytochemicals for cytotoxic activity to human cancer cells and identified Soyasapogenol-A (Snol-A) as a potent candidate anti-cancer compound. Interestingly, Soyasapogenin-I (Snin-I) was ineffective. Viability assays endorsed toxicity of Snol-A to a wide variety of cancer cells. Of note, wild type p53 deficient cancer cells (SKOV-3 and Saos-2) also showed potent growth inhibitory effect. Molecular analyses demonstrated that it targets CARF yielding transcriptional upregulation of p21 WAF1 (an inhibitor of cyclin-dependent kinases) and downregulation of its effector proteins, CDK2, CDK-4, Cyclin A and Cyclin D1. Targeting of CARF by Snol-A also caused (i) downregulation of pATR-Chk1 signaling leading to caspase-mediated apoptosis and (ii) inactivation of β-catenin/Vimentin/hnRNPKmediated EMT signaling resulting in decrease in migration and invasion of cancer cells. In in vivo assays, Snol-A caused suppression of tumor growth in subcutaneous xenograft model and inhibited lung metastasis in tail vein injection model. Taken together, we demonstrate that Snol-A is a natural inhibitor of CARF and may be recruited as a potent anti-tumor and anti-metastasis compound for treatment of p53-deficient aggressive malignancies. Cancer chemotherapy has made a remarkable progress in last two decades. However, conventional chemotherapeutic drugs are known to produce serious health issues, by affecting the normal body functions, and QOL of patients during and after the treatment 1. These adverse side-effects along with the emerging drug resistance 2 , have underlined a need of safe and effective alternatives for cancer treatment 2. Natural compounds, due to their easy availability, safety, and economic aspects have recently got much attention of researchers. Anticancer properties of several natural compounds have been demonstrated and their mechanism(s) of action against malignant disease are beginning to be revealed 3-7. Triterpenoids include a diverse group of triterpenes with more than 100 distinct skeletons 8. Ursolic acid, oleanolic acid, saponins and betulinic acid are among the well-known triterpenes and have been shown to possess a wide variety of biological activities such as anti-inflammatory 9 , anti-allergic 10 , cardio protective 11 , anti-diabetic 12 , metabolic regulation activities 13 and anti-cancer 14,15. Soybean has been a preferred source of protein in dietary regime worldwide 16. Soy-based food alternatives have attained a larger recognition, owing to their health benefits as functional food 17. In Asian sub-continent, especially Japan, soy-based foods e.g. tofu, miso, soy sauce, milk, natto, edamame are major source of daily protein intake 18. In above soy-based foods, soyasaponins were found to constitute a larger proportion as compared to the soyasapogenols (1:85) 19. However, long-term maturated miso was shown to retain a higher content of soyasapogenols 19. Amongst soyasapogenols, content of soyasapogenol B has been found to be higher as compared to soyasapogenol A 19. Several studies on ...

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