Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway

Farzad Rahmani; Milad Hashemzehi; Amir Avan; Farnaz Barneh; Fereshteh Asgharzadeh; Reyhaneh Moradi Marjaneh; Atena Soleimani; Mohammadreza Parizadeh; Gordon A. Ferns; Majid Ghayour Mobarhan; Mikhail Ryzhikov; Amir Reza Afshari; Mohammad Reza Ahmadian; Elisa Giovannetti; Mohieddin Jafari; Majid Khazaei; Seyed Mahdi Hassanian

doi:10.1016/j.cellsig.2021.110069

Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway

Farzad Rahmani
, Milad Hashemzehi
, Amir Avan
, Farnaz Barneh
, Fereshteh Asgharzadeh
, Reyhaneh Moradi Marjaneh
, Atena Soleimani
, Mohammadreza Parizadeh
, Gordon A. Ferns
, Majid Ghayour Mobarhan
, Mikhail Ryzhikov
, Amir Reza Afshari
, Mohammad Reza Ahmadian
, Elisa Giovannetti
, Mohieddin Jafari
, Majid Khazaei^*
, Seyed Mahdi Hassanian^*

^*Corresponding author for this work

Iranshahr University of Medical Sciences
Mashhad University of Medical Sciences
Shahid Beheshti University of Medical Sciences
Brighton and Sussex Medical School
Washington University School of Medicine
Heinrich Heine University Düsseldorf
University of Pisa
University of Helsinki

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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.

Original language	English
Article number	110069
Journal	Cellular signalling
Volume	85
DOIs	https://doi.org/10.1016/j.cellsig.2021.110069
Publication status	Published - 1 Sept 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Colon cancer
Ras signaling
Rigoserib

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10.1016/j.cellsig.2021.110069

Rigosertib-elicits-potent-anti-tumor-responses-in-colorectal-cancer-by-inhibiting-ras-signaling-pathway.pdfFinal published version, 4.76 MBLicence: Taverne

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Rahmani, F., Hashemzehi, M., Avan, A., Barneh, F., Asgharzadeh, F., Moradi Marjaneh, R., Soleimani, A., Parizadeh, M., Ferns, G. A., Ghayour Mobarhan, M., Ryzhikov, M., Afshari, A. R., Ahmadian, M. R., Giovannetti, E., Jafari, M., Khazaei, M., & Hassanian, S. M. (2021). Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway. Cellular signalling, 85, Article 110069. https://doi.org/10.1016/j.cellsig.2021.110069

@article{44e9d5e4453147148782278ea0931008,

title = "Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway",

abstract = "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.",

keywords = "Colon cancer, Ras signaling, Rigoserib",

author = "Farzad Rahmani and Milad Hashemzehi and Amir Avan and Farnaz Barneh and Fereshteh Asgharzadeh and \{Moradi Marjaneh\}, Reyhaneh and Atena Soleimani and Mohammadreza Parizadeh and Ferns, \{Gordon A.\} and \{Ghayour Mobarhan\}, Majid and Mikhail Ryzhikov and Afshari, \{Amir Reza\} and Ahmadian, \{Mohammad Reza\} and Elisa Giovannetti and Mohieddin Jafari and Majid Khazaei and Hassanian, \{Seyed Mahdi\}",

note = "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: {\textcopyright} 2021 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = sep,

day = "1",

doi = "10.1016/j.cellsig.2021.110069",

language = "English",

volume = "85",

journal = "Cellular signalling",

issn = "0898-6568",

publisher = "Elsevier Inc.",

}

Rahmani, F, Hashemzehi, M, Avan, A, Barneh, F, Asgharzadeh, F, Moradi Marjaneh, R, Soleimani, A, Parizadeh, M, Ferns, GA, Ghayour Mobarhan, M, Ryzhikov, M, Afshari, AR, Ahmadian, MR, Giovannetti, E, Jafari, M, Khazaei, M & Hassanian, SM 2021, 'Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway', Cellular signalling, vol. 85, 110069. https://doi.org/10.1016/j.cellsig.2021.110069

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 - https://www.scopus.com/pages/publications/85111786208

U2 - 10.1016/j.cellsig.2021.110069

DO - 10.1016/j.cellsig.2021.110069

M3 - Article

C2 - 34214591

SN - 0898-6568

VL - 85

JO - Cellular signalling

JF - Cellular signalling

M1 - 110069

ER -

Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway

Abstract

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Keywords

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