Proliferative and anti-proliferative effects of retinoic acid at doses similar to endogenous levels in Leydig MLTC-1/R2C/TM-3 cells.
BACKGROUND
Vitamin A is suggested to be protective against oxidative stress. However, different authors observed pro-oxidant effects of retinoids both in experimental works and clinical trials. These discordances are the bases for the investigation of the proliferative and anti-proliferative properties of retinoic acid (RA) in biological systems.


METHODS
Cell viability is determined with the MTT assay. Oxidative stress parameters are detected measuring catalase (CAT) and glutathione S-transferase (GST) enzymatic activities. FABP5 mRNA levels are measured by RT-PCR. Autophagy and apoptosis are analyzed by Monodansylcadaverine (MDC) staining and TUNEL assay, respectively.


CONCLUSIONS
RA, at nutraceutic/endogenous doses (10-200 nM), increases cell viability of testes tumor Leydig cell lines (MLTC-1 and R2C) and modulates antioxidant enzyme activities, as CAT and GST. RA is able to induce proliferation through non-classical and redox-dependent mechanisms accompanied by increased levels of FABP5 mRNA. The redox environment of the cell is currently thought to be extremely important for controlling either apoptosis or autophagy. Apoptosis occurs at pharmacological doses, while autophagy, which plays a critical role in removing damaged or surplus organelles in order to maintain cellular homeostasis, is triggered at the critical concentration of 500 nM RA, both in normal and tumoral cells. Slight variations of RA concentrations are evaluated as a threshold value to distinguish between the proliferative or anti-proliferative effects.


CONCLUSIONS
Although retinoids have a promising role as antineoplastic agents, physiological levels of RA play a key role in Leydig cancer progression, fostering proliferation and growth of testicular tumoral mass.
Perri
Mariarita
M
Dipartimento Farmaco-Biologico, Laboratorio di Biochimica, Edificio Polifunzionale, Università della Calabria, 87036 Rende (CS), Italy.
Pingitore
Attilio
A
Cione
Erika
E
Vilardi
Emma
E
Perrone
Valentina
V
Genchi
Giuseppe
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002415:Cats; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007984:Leydig Cell Tumor / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D007985:Leydig Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D000975:Antioxidants; D014212:Tretinoin