TY - JOUR
T1 - Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway
AU - Rahmani, Farzad
AU - Hashemzehi, Milad
AU - Avan, Amir
AU - Barneh, Farnaz
AU - Asgharzadeh, Fereshteh
AU - Moradi Marjaneh, Reyhaneh
AU - Soleimani, Atena
AU - Parizadeh, Mohammadreza
AU - Ferns, Gordon A.
AU - Ghayour Mobarhan, Majid
AU - Ryzhikov, Mikhail
AU - Afshari, Amir Reza
AU - Ahmadian, Mohammad Reza
AU - Giovannetti, Elisa
AU - Jafari, Mohieddin
AU - Khazaei, Majid
AU - Hassanian, Seyed Mahdi
N1 - Funding Information:
This study was supported by grants awarded by the Mashhad University of Medical Sciences (Grant No. 951406 ), and the Biotechnology Development Council of the Islamic Republic of Iran (Grant No. 960301 ) to S.M.H. and National Institute for Medical Research Development (Grant No. 965391 ) to M.K., Student Research Committee of Mashhad University of Medical Sciences (Grant No. 961662 ) to F.R., and the European Network on Noonan Syndrome and Related Disorders (NSEuroNet, 01GM1602B ); the German Federal Ministry of Education and Research (BMBF) – German Network of RASopathy Research (GeNeRARe, 01GM1902C ).
Publisher Copyright:
© 2021 Elsevier Inc.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Background: The therapeutic potency of Rigosertib (RGS) in the treatment of the myelodysplastic syndrome has been investigated previously, but little is known about its mechanisms of action. Methods: The present study integrates systems and molecular biology approaches to investigate the mechanisms of the anti-tumor effects of RGS, either alone or in combination with 5-FU in cellular and animal models of colorectal cancer (CRC). Results: The effects of RGS were more pronounced in dedifferentiated CRC cell types, compared to cell types that were epithelial-like. RGS inhibited cell proliferation and cell cycle progression in a cell-type specific manner, and that was dependent on the presence of mutations in KRAS, or its down-stream effectors. RGS increased both early and late apoptosis, by regulating the expression of p53, BAX and MDM2 in tumor model. We also found that RGS induced cell senescence in tumor tissues by increasing ROS generation, and impairing oxidant/anti-oxidant balance. RGS also inhibited angiogenesis and metastatic behavior of CRC cells, by regulating the expression of CD31, E-cadherin, and matrix metalloproteinases-2 and 9. Conclusion: Our findings support the therapeutic potential of this potent RAS signaling inhibitor either alone or in combination with standard regimens for the management of patients with CRC.
AB - Background: The therapeutic potency of Rigosertib (RGS) in the treatment of the myelodysplastic syndrome has been investigated previously, but little is known about its mechanisms of action. Methods: The present study integrates systems and molecular biology approaches to investigate the mechanisms of the anti-tumor effects of RGS, either alone or in combination with 5-FU in cellular and animal models of colorectal cancer (CRC). Results: The effects of RGS were more pronounced in dedifferentiated CRC cell types, compared to cell types that were epithelial-like. RGS inhibited cell proliferation and cell cycle progression in a cell-type specific manner, and that was dependent on the presence of mutations in KRAS, or its down-stream effectors. RGS increased both early and late apoptosis, by regulating the expression of p53, BAX and MDM2 in tumor model. We also found that RGS induced cell senescence in tumor tissues by increasing ROS generation, and impairing oxidant/anti-oxidant balance. RGS also inhibited angiogenesis and metastatic behavior of CRC cells, by regulating the expression of CD31, E-cadherin, and matrix metalloproteinases-2 and 9. Conclusion: Our findings support the therapeutic potential of this potent RAS signaling inhibitor either alone or in combination with standard regimens for the management of patients with CRC.
KW - Colon cancer
KW - Ras signaling
KW - Rigoserib
UR - http://www.scopus.com/inward/record.url?scp=85111786208&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2021.110069
DO - 10.1016/j.cellsig.2021.110069
M3 - Article
C2 - 34214591
VL - 85
JO - Cellular Signalling
JF - Cellular Signalling
SN - 0898-6568
M1 - 110069
ER -