DNA-PK, Nuclear mTOR, and the Androgen Pathway in Prostate Cancer

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Prostate cancer (PCa) growth is driven by androgen and its receptor (AR).
• Understanding AR's role in PCa progression and therapy resistance is crucial for new treatments.
• The phosphatidylinositol 3-kinase-like protein kinase (PIKK) family members, DNA-PK and mTOR, are implicated in cancer signaling.

Purpose of the Study:

• To review the noncanonical roles of DNA-PK and mTOR as transcription coregulators of the AR in PCa cells.
• To highlight the common features and similarities between DNA-PK and mTOR in modulating AR activity.
• To provide an outlook on translating these findings into novel PCa management and treatment strategies.

Main Methods:

• Literature review focusing on DNA-PK, mTOR, and AR signaling in prostate cancer.
• Analysis of common features and shared mechanisms of DNA-PK and mTOR in AR regulation.
• Synthesis of current knowledge on PIKK family kinases in PCa pathogenesis.

Main Results:

• DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR) directly modulate AR activity on chromatin in PCa cells.
• These kinases share common features and act as transcription coregulators for the AR.
• The interplay between DNA-PK, mTOR, and AR presents potential therapeutic vulnerabilities.

Conclusions:

• DNA-PK and mTOR play significant noncanonical roles in AR-driven prostate cancer.
• Targeting the interaction between these PIKKs and the AR may offer novel therapeutic avenues.
• Further research into these pathways could lead to improved strategies for managing advanced PCa.