TY - JOUR
T1 - IMPA1-derived inositol maintains stemness in castration-resistant prostate cancer via IMPDH2 activation
AU - Hsu, Che Chia
AU - Wang, Guihua
AU - Li, Chien Feng
AU - Zhang, Xian
AU - Cai, Zhen
AU - Chen, Tingjin
AU - Pan, Bo Syong
AU - Manne, Rajesh Kumar
AU - Deep, Gagan
AU - Gu, Haiwei
AU - Wang, Yuzhuo
AU - Peng, Danni
AU - Penugurti, Vasudevarao
AU - Zhou, Xiaobo
AU - Xu, Zhigang
AU - Chen, Zhongzhu
AU - Chen, Ming
AU - Armstrong, Andrew J.
AU - Huang, Jiaoti
AU - Li, Hong Yu
AU - Lin, Hui Kuan
N1 - Publisher Copyright:
© 2024 Hsu et al.
PY - 2024/11/4
Y1 - 2024/11/4
N2 - Acquisition of prostate cancer stem cells (PCSCs) manifested during androgen ablation therapy (ABT) contributes to castration-resistant prostate cancer (CRPC). However, little is known about the specific metabolites critically orchestrating this process. Here, we show that IMPA1-derived inositol enriched in PCSCs is a key metabolite crucially maintaining PCSCs for CRPC progression and ABT resistance. Notably, conditional Impa1 knockout in the prostate abrogates the pool and properties of PCSCs to orchestrate CRPC progression and prolong the survival of TRAMP mice. IMPA1-derived inositol serves as a cofactor that directly binds to and activates IMPDH2, which synthesizes guanylate nucleotides for maintaining PCSCs with ARlow/− features leading to CRPC progression and ABT resistance. IMPA1/inositol/IMPDH2 axis is upregulated in human prostate cancer, and its overexpression predicts poor survival outcomes. Genetically and pharmacologically targeting the IMPA1/ inositol/IMPDH2 axis abrogates CRPC and overcomes ABT resistance in various CRPC xenografts, patient-derived xenograft (PDX) tumor models, and TRAMP mouse models. Our study identifies IMPDH2 as an inositol sensor whose activation by inositol represents a key mechanism for maintaining PCSCs for CRPC and ABT resistance.
AB - Acquisition of prostate cancer stem cells (PCSCs) manifested during androgen ablation therapy (ABT) contributes to castration-resistant prostate cancer (CRPC). However, little is known about the specific metabolites critically orchestrating this process. Here, we show that IMPA1-derived inositol enriched in PCSCs is a key metabolite crucially maintaining PCSCs for CRPC progression and ABT resistance. Notably, conditional Impa1 knockout in the prostate abrogates the pool and properties of PCSCs to orchestrate CRPC progression and prolong the survival of TRAMP mice. IMPA1-derived inositol serves as a cofactor that directly binds to and activates IMPDH2, which synthesizes guanylate nucleotides for maintaining PCSCs with ARlow/− features leading to CRPC progression and ABT resistance. IMPA1/inositol/IMPDH2 axis is upregulated in human prostate cancer, and its overexpression predicts poor survival outcomes. Genetically and pharmacologically targeting the IMPA1/ inositol/IMPDH2 axis abrogates CRPC and overcomes ABT resistance in various CRPC xenografts, patient-derived xenograft (PDX) tumor models, and TRAMP mouse models. Our study identifies IMPDH2 as an inositol sensor whose activation by inositol represents a key mechanism for maintaining PCSCs for CRPC and ABT resistance.
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U2 - 10.1084/jem.20231832
DO - 10.1084/jem.20231832
M3 - Article
C2 - 39470689
AN - SCOPUS:85208081828
SN - 0022-1007
VL - 221
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
M1 - e20231832
ER -