TY - JOUR
T1 - Soyasapogenol-A targets CARF and results in suppression of tumor growth and metastasis in p53 compromised cancer cells
AU - Omar, Amr
AU - Kalra, Rajkumar Singh
AU - Putri, Jayarani
AU - Elwakeel, Ahmed Abdelmageed Saad Ahmed
AU - C. Kaul, Sunil
AU - Wadhwa, Renu
N1 - Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
PY - 2020/4/14
Y1 - 2020/4/14
N2 - 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 p21WAF1 (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/hnRNPK-mediated 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.
AB - 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 p21WAF1 (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/hnRNPK-mediated 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.
UR - http://www.scopus.com/inward/record.url?scp=85083502257&partnerID=8YFLogxK
U2 - 10.1038/s41598-020-62953-5
DO - 10.1038/s41598-020-62953-5
M3 - Article
SN - 2045-2322
VL - 10
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 6323
ER -