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Alpha-Lipoic Acid Reduces Cell Growth, Inhibits Autophagy, and Counteracts Prostate Cancer Cell Migration and Invasion: Evidence from In Vitro Studies.

Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Græcia", 88100 Catanzaro, Italy. Laboratory of Immunology, Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Græcia", 88100 Catanzaro, Italy. Cellular and Molecular Cardiovascular Pathophysiology Laboratory, Department of Biology, University of Calabria, 87036 Rende, Italy. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy. Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036 Rende, Italy. Division of Urology, Department of Surgery, Annunziata Hospital, 87100 Cosenza, Italy. Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy. Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, 20133 Milan, Italy. Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS Istituto Auxologico Italiano, 20145 Milan, Italy.

International journal of molecular sciences. 2023;(23)
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Abstract

Alpha-lipoic acid (ALA) is a natural antioxidant dithiol compound, exerting antiproliferative and antimetastatic effects in various cancer cell lines. In our study, we demonstrated that ALA reduces the cell growth of prostate cancer cells LNCaP and DU-145. Western blot results revealed that in both cancer cells, ALA, by upregulating pmTOR expression, reduced the protein content of two autophagy initiation markers, Beclin-1 and MAPLC3. Concomitantly, MTT assays showed that chloroquine (CQ) exposure, a well-known autophagy inhibitor, reduced cells' viability. This was more evident for treatment using the combination ALA + CQ, suggesting that ALA can reduce cells' viability by inhibiting autophagy. In addition, in DU-145 cells we observed that ALA affected the oxidative/redox balance system by deregulating the KEAP1/Nrf2/p62 signaling pathway. ALA decreased ROS production, SOD1 and GSTP1 protein expression, and significantly reduced the cytosolic and nuclear content of the transcription factor Nrf2, concomitantly downregulating p62, suggesting that ALA disrupted p62-Nrf2 feedback loop. Conversely, in LNCaP cells, ALA exposure upregulated both SOD1 and p62 protein expression, but did not affect the KEAP1/Nrf2/p62 signaling pathway. In addition, wound-healing, Western blot, and immunofluorescence assays evidenced that ALA significantly reduced the motility of LNCaP and DU-145 cells and downregulated the protein expression of TGFβ1 and vimentin and the deposition of fibronectin. Finally, a soft agar assay revealed that ALA decreased the colony formation of both the prostate cancer cells by affecting the anchorage independent growth. Collectively, our in vitro evidence demonstrated that in prostate cancer cells, ALA reduces cell growth and counteracts both migration and invasion. Further studies are needed in order to achieve a better understanding of the underlined molecular mechanisms.