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Sphingosine kinase 1 pathway is involved in melatonin-induced HIF-1α inactivation in hypoxic PC-3 prostate cancer

Sung-Yun Cho1, Hyo-Jeong Lee, Soo-Jin Jeong

  • 1College of Oriental Medicine, Kyung Hee University, Seoul, South Korea Yonsei University School of Medicine, Seoul, South Korea.

Journal of Pineal Research
|March 12, 2011
PubMed

Insights

Melatonin reduces prostate cancer growth by inhibiting Sphingosine Kinase 1 (SPHK1) and hypoxia-inducible factor 1-alpha (HIF-1α) accumulation, particularly under hypoxic conditions.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Sphingosine kinase 1 (SPHK1) is a key regulator of hypoxia-inducible factor 1-alpha (HIF-1α), influencing cell growth, survival, invasion, angiogenesis, and carcinogenesis.
  • Prostate cancer cells (PC-3) exhibit complex biological activities under hypoxic conditions, often involving HIF-1α stabilization.

Purpose of the Study:

  • To elucidate the biological mechanisms of melatonin in PC-3 prostate cancer cells under hypoxia, focusing on the SPHK1 pathway.
  • To investigate the role of SPHK1 in melatonin-mediated inhibition of HIF-1α accumulation.

Main Methods:

  • Investigated the effects of melatonin on HIF-1α stability, SPHK1 activity, and the AKT/GSK-3β signaling pathway in PC-3 cells under hypoxia.
  • Utilized small interfering RNA (siRNA) targeting SPHK1 and a sphingosine kinase inhibitor (SKI) to assess their impact on HIF-1α, phospho-AKT, and VEGF.
  • Examined the role of reactive oxygen species (ROS) using the scavenger N-acetylcysteine.

Main Results:

  • Melatonin inhibited HIF-1α stability and decreased SPHK1 activity in PC-3 cells under hypoxia in a time- and concentration-dependent manner.
  • Melatonin suppressed the AKT/GSK-3β signaling pathway, which is involved in HIF-1α stabilization via the von Hippel-Lindau tumor suppressor protein.
  • siRNA-SPHK1 and SKI treatment blocked HIF-1α, phospho-AKT, and VEGF expression, confirming SPHK1's role in melatonin's effects.
  • N-acetylcysteine enhanced melatonin's inhibitory effects on HIF-1α expression and SPHK1 activity, indicating ROS involvement.

Conclusions:

  • Melatonin effectively suppresses HIF-1α accumulation in PC-3 prostate cancer cells under hypoxia.
  • This suppression is mediated through the inhibition of the SPHK1 pathway and reduction of ROS generation.
  • The findings highlight a novel mechanism by which melatonin exerts anti-cancer effects in prostate cancer.

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