Loss of Kelch-like ECH-associated protein 1 Function in Prostate Cancer Cells Contributes to Chemoresistance and Radioresistance

Prostate cancer cells with defective Kelch-like ECH-associated protein 1 (Keap1) function exhibit increased resistance to chemotherapy and radiation, enabling tumor growth and proliferation. Research led by P. Zhang and colleagues at the Johns Hopkins University's Sidney Kimmel Comprehensive Cancer Center has shed light on the mechanisms underlying this phenomenon. The investigators detected loss-of-function mutations in the Keap1 gene, which resulted in non-conservative amino acid substitutions in prostate cancer cells. This led to the activation of the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway, promoting tumor growth and resistance to chemotherapeutic agents.

Key Takeaways:

• Loss-of-function mutations in the Keap1 gene were detected in prostate cancer cells, leading to non-conservative amino acid substitutions.
• The activation of Nrf2 and its downstream electrophile/drug detoxification pathway was significantly increased in cells with defective Keap1 function.
• Inhibition of Nrf2 expression in prostate cancer cells attenuated the expression of glutathione, thioredoxin, and drug efflux pathways involved in counteracting electrophiles and detoxification of drugs.
• Targeting the Nrf2 pathway may provide a novel strategy to enhance chemotherapy and radiotherapy responsiveness and ameliorate tumor growth and tumorigenicity.
• The researchers suggested that inhibition of Nrf2 could suppress in vitro and in vivo tumor growth of prostate cancer cells.
• The study's findings imply that increased Nrf2 activity is a key factor in chemoresistance and radioresistance in prostate cancer cells.

Statistics:

• 5-aza-deoxycytidine treatment significantly increased Keap1 mRNA levels in DU-145 cells, indicating a correlation between epigenetic regulation and Keap1 dysfunction.
• DU-145 cells with constitutive expression of Nrf2 short hairpin RNA had lower levels of total glutathione (55% decrease) and higher levels of intracellular reactive oxygen species (26% increase).
• Inhibition of Nrf2 significantly suppressed in vitro and in vivo tumor growth of DU-145 prostate cancer cells by 73% and 62%, respectively.

Sources:

• Zhang, P., et al. (2010). Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth. Molecular Cancer Therapeutics, 9(2), 336-346.