ROS-Dependent ER Stress and Autophagy Mediate the Anti-Tumor Effects of Tributyltin (IV) Ferulate in Colon Cancer Cells

• Published in: International journal of molecular sciences Vol. 21; no. 21; p. 8135
• Main Authors: Celesia, Adriana, Morana, Ornella, Fiore, Tiziana, Pellerito, Claudia, D'Anneo, Antonella, Lauricella, Marianna, Carlisi, Daniela, De Blasio, Anna, Calvaruso, Giuseppe, Giuliano, Michela, Emanuele, Sonia
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 30.10.2020; MDPI AG
• Subjects: Apoptosis; autophagic cell death; Autophagy; Cell Proliferation; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Gene Expression Regulation, Neoplastic; Humans; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; oxidative stress; Oxidative Stress - drug effects; Reactive Oxygen Species - metabolism; ROS; Trialkyltin Compounds - pharmacology; tributyltin (IV) derivative; Tumor Cells, Cultured; autophagic cell death; tributyltin (IV) derivative; endoplasmic reticulum stress; oxidative stress; ROS
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21218135

Organotin compounds represent potential cancer therapeutics due to their pro-apoptotic action. We recently synthesized the novel organotin ferulic acid derivative tributyltin (IV) ferulate (TBT-F) and demonstrated that it displays anti-tumor properties in colon cancer cells related with autophagic cell death. The purpose of the present study was to elucidate the mechanism of TBT-F action in colon cancer cells. We specifically show that TBT-F-dependent autophagy is determined by a rapid generation of reactive oxygen species (ROS) and correlated with endoplasmic reticulum (ER) stress. TBT-F evoked nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated antioxidant response and Nrf2 silencing by RNA interference markedly increased the anti-tumor efficacy of the compound. Moreover, as a consequence of ROS production, TBT-F increased the levels of glucose regulated protein 78 (Grp78) and C/EBP homologous protein (CHOP), two ER stress markers. Interestingly, Grp78 silencing produced significant decreasing effects on the levels of the autophagic proteins p62 and LC3-II, while only p62 decreased in CHOP-silenced cells. Taken together, these results indicate that ROS-dependent ER stress and autophagy play a major role in the TBT-F action mechanism in colon cancer cells and open a new perspective to consider the compound as a potential candidate for colon cancer treatment.