Mitochondrial Unfolded Protein Response-Dependent β-Catenin Signaling Promotes Neuroendocrine Prostate Cancer

Academic Background

Prostate cancer is the second most commonly diagnosed cancer in American men, second only to skin cancer. Although current treatments, such as androgen deprivation therapy (ADT), can induce remission in prostate cancer, almost all cases eventually progress to castration-resistant prostate cancer (CRPC). CRPC is no longer sensitive to inhibitors of the androgen receptor (AR) signaling pathway, highlighting the urgent need for the development of new therapeutic targets. Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of CRPC, often induced by ADT treatment. NEPC cells lose AR expression and rely on other signaling pathways for survival, exhibiting high metastatic potential. Although platinum-based chemotherapy is initially effective against NEPC, patients eventually develop resistance, leading to disease progression.

The mitochondrial unfolded protein response (UPRmt) is a critical mechanism for maintaining mitochondrial protein homeostasis under stress conditions. However, the role of UPRmt in prostate cancer, particularly in NEPC, remains unclear. This study aims to explore the mechanisms by which UPRmt contributes to NEPC and evaluate its potential as a therapeutic target.

Source of the Paper

This paper was co-authored by Jordan Alyse Woytash, Rahul Kumar, Ajay K. Chaudhary, and others, from institutions such as the Roswell Park Comprehensive Cancer Center and Aarhus University. The paper was published in 2024 in the journal Oncogene, with the DOI 10.1038/s41388-024-03261-4.

Research Process and Results

1. Mitochondrial Dysfunction in Neuroendocrine Prostate Tumors

The study first used a mouse model (TRAMP) to reveal that the activity of mitochondrial oxidative phosphorylation (OXPHOS) complexes II, IV, and V was significantly reduced in NEPC tumors, indicating severe mitochondrial dysfunction. Additionally, the expression of nuclear-encoded OXPHOS proteins was upregulated in NEPC tumors, suggesting the presence of a mitochondrial stress response. These results indicate that NEPC tumors maintain mitochondrial function and cell survival by activating UPRmt.

2. Upregulation of UPRmt in NEPC

Using multiple mouse models and clinical data analysis, the study found that the main UPRmt chaperone protein, HSP60, was significantly upregulated in NEPC tumors. HSP60 expression was closely associated with tumor aggressiveness, metastatic potential, and response to ADT. Furthermore, HSP60 expression was positively correlated with the activation of the β-catenin signaling pathway, suggesting that HSP60 promotes NEPC progression by regulating β-catenin signaling.

3. HSP60 Regulates NEPC Markers

The study found that genetic or pharmacological inhibition of HSP60 could reverse the neuroendocrine phenotype of NEPC cells, driving them toward a more epithelial-like state. Inhibition of HSP60 also significantly reduced the expression of β-catenin and its downstream target c-Myc, further confirming that HSP60 promotes NEPC progression by regulating β-catenin signaling.

4. HSP60 Inhibition Reduces Migration and Invasion in Prostate Cancer Cells

Through in vitro experiments, the study found that inhibition of HSP60 significantly reduced the migration and invasion capabilities of NEPC cells. Additionally, inhibition of HSP60 reduced tumor invasiveness in mouse models, further supporting the critical role of HSP60 in NEPC metastasis.

5. HSP60 Inhibition Reduces Mitochondrial OXPHOS Function

Inhibition of HSP60 significantly reduced the expression of mitochondrial OXPHOS complexes and ATP production, indicating that HSP60 promotes NEPC survival by regulating mitochondrial metabolism. Furthermore, inhibition of β-catenin also significantly reduced mitochondrial function, suggesting that HSP60 regulates mitochondrial metabolism through β-catenin.

6. HSP60 Inhibition Sensitizes CRPC Cells to Cisplatin

The study found that inhibition of HSP60 significantly enhanced the sensitivity of NEPC cells to cisplatin. In cisplatin-resistant cells, the expression of HSP60 and mitochondrial OXPHOS proteins was significantly upregulated, and inhibition of HSP60 reversed this resistance, making the cells sensitive to cisplatin again.

Conclusions and Significance

This study is the first to reveal that HSP60 promotes NEPC progression and drug resistance by regulating β-catenin signaling and mitochondrial metabolism. Inhibition of HSP60 not only reverses the neuroendocrine phenotype of NEPC cells but also enhances their sensitivity to cisplatin. These findings provide new therapeutic targets for NEPC, particularly for patients who have developed resistance to existing therapies.

Research Highlights

1. Key Role of HSP60 in NEPC: HSP60 promotes NEPC progression and drug resistance by regulating β-catenin signaling and mitochondrial metabolism.
2. HSP60 as a Therapeutic Target: Inhibition of HSP60 reverses the neuroendocrine phenotype of NEPC cells and enhances their sensitivity to cisplatin.
3. Relationship Between Mitochondrial Metabolism and NEPC: Dysregulation of mitochondrial OXPHOS function is a key feature of NEPC, and HSP60 maintains NEPC survival by regulating mitochondrial metabolism.

Research Value

This study not only reveals the critical role of HSP60 in NEPC but also provides new insights for the treatment of NEPC. Inhibition of HSP60 may become a new therapeutic strategy, especially for patients who have developed resistance to existing therapies. Additionally, this study offers new perspectives on the role of mitochondrial metabolism in cancer progression.