Melatonin uptake in prostate cancer cells: intracellular transport versus simple passive diffusion

Authors

  • David Hevia,

    1. Departamento de Morfología y Biología Celular, School of Medicine, University of Oviedo
    2. Instituto Universitario Oncológico del Principado de Asturias (IUOPA)
    Search for more papers by this author
    • *

      These authors contributed equally to this work.

  • Rosa M. Sainz,

    1. Departamento de Morfología y Biología Celular, School of Medicine, University of Oviedo
    2. Instituto Universitario Oncológico del Principado de Asturias (IUOPA)
    Search for more papers by this author
    • *

      These authors contributed equally to this work.

  • Domingo Blanco,

    1. Departamento de Química Fisica Analítica, School of Chemistry, University of Oviedo, Spain
    Search for more papers by this author
  • Isabel Quirós,

    1. Departamento de Morfología y Biología Celular, School of Medicine, University of Oviedo
    2. Instituto Universitario Oncológico del Principado de Asturias (IUOPA)
    Search for more papers by this author
  • Dun-Xian Tan,

    1. Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
    Search for more papers by this author
  • Carmen Rodríguez,

    1. Departamento de Morfología y Biología Celular, School of Medicine, University of Oviedo
    2. Instituto Universitario Oncológico del Principado de Asturias (IUOPA)
    Search for more papers by this author
  • Juan C. Mayo

    1. Departamento de Morfología y Biología Celular, School of Medicine, University of Oviedo
    2. Instituto Universitario Oncológico del Principado de Asturias (IUOPA)
    Search for more papers by this author

Address reprint requests to Juan Carlos Mayo, Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, C/ Julian Claveria, 6, 33006 Oviedo, Spain.
E-mail: mayojuan@uniovi.es

Abstract

Abstract:  Melatonin, an indole mainly synthesized in the pineal gland during the dark phase, plays a role as an endogenous antioxidant and an anticancer agent in many tumors. Melatonin, at pharmacological concentrations, inhibits cell growth and induces neuroendocrine differentiation in prostate cancer cells. Classically it has been considered that melatonin enters freely into most of cells by passive diffusion through the cell membrane; however, there are few studies examining how melatonin is taken up by cancer cells. The aim of the present paper was to study the uptake of melatonin into human androgen-dependent LNCaP and androgen-independent PC-3 prostate cancer cells. Increased concentrations of melatonin induced a rapid and transitory rise in intracellular melatonin content in both cell types, with a peak of maximal content at 6 hr after melatonin addition, following a rhythmic uptake; melatonin was found in both cytoplasm and nuclear fractions. Inhibition of protein or RNA synthesis partially blocked melatonin uptake in both cell lines. Interestingly, melatonin pulse incubation led to a higher uptake after four cycles of pulse incubation. Neither extracellular Ca2+/K+ alterations nor the presence of bovine serum albumin or charcoal-stripped serum modified the profile of melatonin uptake. On the contrary, chemical binding of melatonin to BSA totally prevented melatonin from entering into cells. The present data support the hypothesis that a facilitated diffusion or an active process rather than simple passive diffusion through the cell membrane is the major mechanism in melatonin uptake by prostate cancer cells and it accounts for its intracellular concentration (350 nm–3.3 μm), which is related to its anti-tumor actions.

Ancillary