TY - JOUR
T1 - Casticin activates Rheb GTPase by binding to residue Trp141 and induces tumor senescence
AU - Su, Tao
AU - Shi, Zhiqiang
AU - Tan, Jincheng
AU - Liu, Linsheng
AU - Zhao, Bingquan
AU - Fan, Xueying
AU - Wang, Caiyan
AU - Kwan, Hiu Yee
AU - Liu, Zhongqiu
N1 - This work was supported by the National Key Research and Development Program of China (2023YFC3502800), Guangzhou Basic and Applied Basic Research Foundation (2025A04J5398), Young Pearl River Scholar of Guangdong Province, Chinese Medicine Guangdong Laboratory (HOL2024PZ042), Characteristic Innovation Projects of Universities in Guangdong Province (2023KTSCX023), the Administration of Traditional Chinese Medicine of Guangdong Province (20241074), HMRF (08193596), GDNSF (2023A1515011811), FNRA-IG (RC-FNRA-IG/20–21/SCM/01) and SFCRG (RC-SFCRG/23–24/SCM/02).
Publisher Copyright:
© 2025 The Authors
PY - 2025/8
Y1 - 2025/8
N2 - Senescence is a state of irreversible growth arrest that can be induced in colorectal cancer (CRC). Developing drugs that can induce senescent CRC cells without promoting stemness can significantly improve treatment outcomes. Our study reveals a unique mechanism by which casticin (CAS) induces senescence in CRC. Importantly, CAS treatment does not induce stemness in CRC, as demonstrated both in vitro and in vivo. Further investigations showed that CAS binds to Rheb protein at residue Trp141, changing the conformation of Rheb protein, increasing its protein stability and activity. Additionally, CAS elevates AMPK activity. Knockdown of Rheb suppresses AMPK activity, indicating that AMPK acts downstream of Rheb. Crucially, inhibiting either Rheb or AMPK completely abolishes CAS-induced senescence in CRC. This study demonstrates that CAS binding to Trp141 activates Rheb GTPase, effectively inducing senescence in CRC through the Rheb/AMPK signaling pathway without promoting cancer cell stemness. This novel discovery highlights the potential for developing herbal-based senescence-inducing agents targeting Rheb for cancer treatments.
AB - Senescence is a state of irreversible growth arrest that can be induced in colorectal cancer (CRC). Developing drugs that can induce senescent CRC cells without promoting stemness can significantly improve treatment outcomes. Our study reveals a unique mechanism by which casticin (CAS) induces senescence in CRC. Importantly, CAS treatment does not induce stemness in CRC, as demonstrated both in vitro and in vivo. Further investigations showed that CAS binds to Rheb protein at residue Trp141, changing the conformation of Rheb protein, increasing its protein stability and activity. Additionally, CAS elevates AMPK activity. Knockdown of Rheb suppresses AMPK activity, indicating that AMPK acts downstream of Rheb. Crucially, inhibiting either Rheb or AMPK completely abolishes CAS-induced senescence in CRC. This study demonstrates that CAS binding to Trp141 activates Rheb GTPase, effectively inducing senescence in CRC through the Rheb/AMPK signaling pathway without promoting cancer cell stemness. This novel discovery highlights the potential for developing herbal-based senescence-inducing agents targeting Rheb for cancer treatments.
KW - Casticin
KW - Colorectal cancer
KW - Rheb GTPase (Trp141), mTORC1-independent
KW - Tumor senescence
UR - https://www.scopus.com/pages/publications/105010958346
UR - https://www.sciencedirect.com/science/article/pii/S1043661825002804?via%3Dihub
U2 - 10.1016/j.phrs.2025.107855
DO - 10.1016/j.phrs.2025.107855
M3 - Journal article
AN - SCOPUS:105010958346
SN - 1043-6618
VL - 218
JO - Pharmacological Research
JF - Pharmacological Research
M1 - 107855
ER -
