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Updated: Oct 2, 2025
Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Reprogramming hormone-sensitive prostate cancer to a lethal neuroendocrine cancer lineage by mitochondrial pyruvate
Huan Xu1, Zhixiao Liu2, Dajun Gao1
1Department of Urology, Shanghai Ninth People's Hospital, Shanghai, China.
Abstract:
Cell lineage reprogramming is the main approach for cancer cells to acquire drug resistance and escape targeted therapy. The use of potent targeted therapies in cancers has led to the development of highly aggressive carcinoma, including neuroendocrine prostate cancer (NEPC). Although metabolic reprogramming has been reported to be essential for tumor growth and energy production, the relationship between metabolic reprogramming and lineage differentiation which can cause hormone therapy resistance has never been reported in prostate cancer (PCa). Moreover, as there is still no efficient therapy for NEPC, it is urgent to reverse this lineage differentiation during the hormone therapy. Here for the first time, we used in vitro and in vivo human PCa models to study the effect of metabolic reprogramming on the lineage differentiation from the androgen receptor (AR)-dependent adenocarcinoma to AR-independent NEPC. This lineage differentiation leads to antiandrogen drug resistance and tumor development. This phenotype is enabled by the loss of mitochondrial pyruvate carrier (MPC), the gate for mitochondrial pyruvate influx, and can be reversed by MPC overexpression. Morphologic and cellular studies also demonstrate that the pyruvate kinase M2 (PKM2) involved epithelium-mesenchymal transition process mediated this lineage alteration. Its inhibition is a potential treatment for MPC-lo tumors. All of these results suggest that metabolic rewiring can act as a starter for increased cellular plasticity which leads to antiandrogen therapy resistance through lineage differentiation. This study provides us with a potent treatment target for therapy-induced, enzalutamide-resistant NE-like prostate cancer.
Insights
Metabolic reprogramming drives prostate cancer (PCa) cells to become neuroendocrine prostate cancer (NEPC), causing hormone therapy resistance. Restoring mitochondrial pyruvate carrier (MPC) function can reverse this aggressive lineage change.
Area of Science:
- Oncology
- Metabolic Pathways
- Cellular Differentiation
Background:
- Cell lineage reprogramming is a key mechanism for cancer cells to develop drug resistance and evade targeted therapies.
- Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer often arising after treatment with targeted therapies.
- Metabolic reprogramming is crucial for tumor growth, but its link to lineage differentiation and hormone therapy resistance in prostate cancer (PCa) remains unexplored.
Purpose of the Study:
- To investigate the role of metabolic reprogramming in the lineage differentiation of prostate cancer from androgen receptor (AR)-dependent adenocarcinoma to AR-independent NEPC.
- To understand how this lineage plasticity contributes to antiandrogen drug resistance and tumor progression.
- To identify potential therapeutic targets for reversing NEPC development and overcoming therapy resistance.
Main Methods:
- Utilized in vitro and in vivo human PCa models to study metabolic reprogramming and lineage differentiation.
- Assessed the impact of mitochondrial pyruvate carrier (MPC) function on NEPC development and drug resistance.
- Investigated the role of pyruvate kinase M2 (PKM2) and epithelial-mesenchymal transition (EMT) in mediating lineage alteration.
Main Results:
- Demonstrated that loss of MPC facilitates lineage differentiation towards NEPC, leading to antiandrogen drug resistance.
- Showed that MPC overexpression can reverse this lineage plasticity and restore sensitivity to therapy.
- Identified PKM2-mediated EMT as a key process in this lineage alteration, suggesting PKM2 inhibition as a potential treatment strategy for MPC-low tumors.
Conclusions:
- Metabolic rewiring, specifically alterations in MPC function, initiates cellular plasticity driving lineage differentiation and antiandrogen therapy resistance in prostate cancer.
- Targeting metabolic pathways, such as inhibiting PKM2 or restoring MPC function, offers a promising therapeutic strategy for combating therapy-induced NEPC and enzalutamide resistance.
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