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Prostaglandins Secreted by Senescent Cells Inhibit Myoblast Differentiation via HRas C-terminal Cysteines
CC BY 4.0 · Indian J Med Paediatr Oncol 2024; 45(S 01): S1-S16
DOI: DOI: 10.1055/s-0044-1788203
*Corresponding author: (e-mail: arvind@instem.res.in).
Abstract
Background: An irreversible cell cycle arrest characterizes senescence. Senescent cells secrete a variety of biomolecules as a secretory phenotype (SASP), altering the microenvironment surrounding the senescent cells. Chemotherapy-mediated senescent myoblasts secrete 15 deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an electrophilic eicosanoid prostaglandin, which inhibits myoblast differentiation via a poorly understood mechanism.
Materials and Methods: We induced senescence in C2C12 mouse myoblasts using Doxorubicin to measure the SASP. We treated myoblasts with 15d-PGJ2 to study the effect on muscle differentiation and the underlying mechanism. We used site-directed mutants to study the role of HRas C-terminal cysteines in 15d-PGJ2-mediated inhibition of myoblast differentiation.
Results: We show that 15d-PGJ2 inhibits the differentiation of myoblasts via activation of the HRas-MAPK pathway. 15d-PGJ2 covalently modifies HRas at Cysteine 184 to alter the intracellular distribution and activity, which is necessary for 15d-PGJ2-mediated inhibition of myoblast differentiation. We also show that altered intracellular distribution of constitutively active HRas affects the downstream signaling.
Conclusion: We hypothesize that alteration in the intracellular distribution and preferential activation of the HRas-MAPK pathway in a C-terminal cysteine-dependent manner is a mechanism by which electrophilic eicosanoid prostaglandins inhibit the differentiation of myoblasts. This is a possible mechanism where the accumulation of senescent cells leads to chemotherapy-induced cachexia.
Publication History
Article published online:
08 July 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
*Corresponding author: (e-mail: arvind@instem.res.in).
Abstract
Background: An irreversible cell cycle arrest characterizes senescence. Senescent cells secrete a variety of biomolecules as a secretory phenotype (SASP), altering the microenvironment surrounding the senescent cells. Chemotherapy-mediated senescent myoblasts secrete 15 deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an electrophilic eicosanoid prostaglandin, which inhibits myoblast differentiation via a poorly understood mechanism.
Materials and Methods: We induced senescence in C2C12 mouse myoblasts using Doxorubicin to measure the SASP. We treated myoblasts with 15d-PGJ2 to study the effect on muscle differentiation and the underlying mechanism. We used site-directed mutants to study the role of HRas C-terminal cysteines in 15d-PGJ2-mediated inhibition of myoblast differentiation.
Results: We show that 15d-PGJ2 inhibits the differentiation of myoblasts via activation of the HRas-MAPK pathway. 15d-PGJ2 covalently modifies HRas at Cysteine 184 to alter the intracellular distribution and activity, which is necessary for 15d-PGJ2-mediated inhibition of myoblast differentiation. We also show that altered intracellular distribution of constitutively active HRas affects the downstream signaling.
Conclusion: We hypothesize that alteration in the intracellular distribution and preferential activation of the HRas-MAPK pathway in a C-terminal cysteine-dependent manner is a mechanism by which electrophilic eicosanoid prostaglandins inhibit the differentiation of myoblasts. This is a possible mechanism where the accumulation of senescent cells leads to chemotherapy-induced cachexia.
No conflict of interest has been declared by the author(s).
Publication History
Article published online:
08 July 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India