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Mitoribosome sensitivity to HSP70 inhibition uncovers metabolic liabilities of castration-resistant prostate cancer
Frank J Echtenkamp1, Ryo Ishida1, Genesis M Rivera-Marquez1
1Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Abstract:
The androgen receptor is a key regulator of prostate cancer and the principal target of current prostate cancer therapies collectively termed androgen deprivation therapies. Insensitivity to these drugs is a hallmark of progression to a terminal disease state termed castration-resistant prostate cancer. Therefore, novel therapeutic options that slow progression of castration-resistant prostate cancer and combine effectively with existing agents are in urgent need. We show that JG-98, an allosteric inhibitor of HSP70, re-sensitizes castration-resistant prostate cancer to androgen deprivation drugs by targeting mitochondrial HSP70 (HSPA9) to suppress aerobic respiration. Rather than impacting androgen receptor stability as previously described, JG-98's primary effect is inhibition of mitochondrial translation, leading to disruption of electron transport chain activity. Although functionally distinct from HSPA9 inhibition, direct inhibition of the electron transport chain with a complex I or II inhibitor creates a similar physiological state capable of re-sensitizing castration-resistant prostate cancer to androgen deprivation therapies. These data identify a significant role for HspA9 in mitochondrial ribosome function and highlight an actionable metabolic vulnerability of castration-resistant prostate cancer.
Insights
JG-98, an HSP70 inhibitor, re-sensitizes castration-resistant prostate cancer to standard therapies by targeting mitochondrial respiration. This approach offers a new strategy for treating advanced prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- Androgen receptor (AR) signaling drives prostate cancer, with therapies targeting AR known as androgen deprivation therapies (ADTs).
- Castration-resistant prostate cancer (CRPC) emerges from insensitivity to ADTs, marking disease progression.
- New therapeutic strategies are crucial for CRPC that can overcome resistance and synergize with existing treatments.
Purpose of the Study:
- To investigate the efficacy of JG-98, an allosteric inhibitor of Heat Shock Protein 70 (HSP70), in re-sensitizing CRPC to ADTs.
- To elucidate the mechanism by which JG-98 affects CRPC cells, focusing on its interaction with mitochondrial HSP70 (HSPA9).
Main Methods:
- Treatment of CRPC models with JG-98 and ADTs.
- Assessment of cellular respiration, mitochondrial translation, and electron transport chain (ETC) activity.
- Comparison of HSPA9 inhibition with direct ETC inhibition.
Main Results:
- JG-98 re-sensitizes CRPC to ADTs by suppressing aerobic respiration via inhibition of mitochondrial HSPA9.
- JG-98's primary mechanism involves inhibiting mitochondrial translation and disrupting ETC activity, not AR stability.
- Direct inhibition of ETC complex I or II mimics JG-98's effect, re-sensitizing CRPC to ADTs.
Conclusions:
- HSPA9 plays a critical role in mitochondrial ribosome function.
- Targeting HSPA9-mediated mitochondrial respiration presents an actionable metabolic vulnerability in CRPC.
- This study identifies a novel therapeutic avenue for overcoming ADT resistance in advanced prostate cancer.
