STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Prostate cancer (PCa) is a leading cause of cancer death in men, with metastatic PCa (mPCa) being a primary driver of lethality.
• The underlying mechanisms of mPCa progression are not fully understood.
• PTEN gene deletion is common in mPCa, and its co-deletion with STAT3 is frequently observed in liquid biopsies.

Purpose of the Study:

• To investigate the role of STAT3 in the development and progression of metastatic prostate cancer.
• To explore the therapeutic potential of metformin in targeting the STAT3 signaling pathway for mPCa treatment.

Main Methods:

• Analysis of genomic co-deletion of PTEN and STAT3 in mPCa patient liquid biopsies.
• Utilizing a Pten-null mouse prostate model to study the effects of Stat3 loss on metastasis.
• Treating STAT3/AR-expressing PCa xenografts and PCa patients with metformin.
• Assessing molecular changes including LKB1/pAMPK, mTORC1/CREB, AR, and PSA levels.

Main Results:

• Loss of Stat3 in a Pten-null mouse model promoted metastasis by reducing LKB1/pAMPK and activating mTOR/CREB.
• Constitutive Stat3 activation suppressed mTORC1/CREB and prevented mPCa.
• Metformin treatment reduced tumor growth, mTORC1/CREB, AR, and PSA levels in PCa xenografts.
• Metformin upregulated STAT3 and reduced mTORC1 in PCa patients with high Gleason grade and type 2 diabetes.
• High CREB expression correlated with worse clinical outcomes and increased risk of PCa relapse and metastasis.

Conclusions:

• STAT3 plays a critical role in controlling metastatic prostate cancer progression through the LKB1/pAMPK/mTORC1/CREB signaling pathway.
• Targeting this pathway with metformin represents a promising novel therapeutic strategy for lethal mPCa.
• STAT3 and CREB are potential biomarkers for predicting PCa outcomes and treatment response.