Reverse transcriptase inhibitors promote the remodelling of nuclear architecture and induce autophagy in prostate...

Area of Science:

• Molecular Biology
• Cancer Research
• Cell Biology

Background:

• LINE-1 retrotransposons and their encoded reverse transcriptase (RT) are emerging cancer targets.
• Nonnucleoside RT inhibitors (NNRTIs) like efavirenz show anti-cancer effects, reducing proliferation and inducing differentiation.
• The precise mechanisms of NNRTIs in cancer cells remain to be fully elucidated.

Purpose of the Study:

• To clarify the molecular mechanisms by which RT inhibitors exert their anti-cancer effects in prostate carcinoma cells.
• To investigate the impact of RT inhibition on cancer cell proliferation, genome integrity, and nuclear architecture.
• To determine the role of autophagy in mediating the antiproliferative effects of RT inhibitors.

Main Methods:

• Exposure of PC3 metastatic prostate carcinoma cells to efavirenz (EFV) and SPV122.2.
• Assessment of cell proliferation, genome damage, nuclear architecture, nuclear lamina integrity, and micronuclei formation.
• Utilizing pharmacological autophagy inhibitors to probe the role of autophagy.
• Comparison with non-cancer cell lines.

Main Results:

• RT inhibitors decreased proliferation and induced genome damage in PC3 cells.
• Nuclear architecture rearrangements, including lamina disruption and micronuclei budding, were observed.
• These changes were reversible upon cessation of RT inhibitor treatment.
• Autophagy was identified as a key mediator of the antiproliferative effect.
• No similar alterations were induced in non-cancer cell lines.

Conclusions:

• RT inhibitors induce significant genotoxicity and nuclear abnormalities in prostate cancer cells.
• Autophagy plays a critical role in the anti-proliferative action of RT inhibitors.
• These findings highlight novel molecular pathways targeted by RT inhibitors in cancer therapy.