Naringenin-Induced Apoptotic Cell Death in Prostate Cancer Cells Is Mediated via the PI3K/AKT and MAPK Signaling Pathways

J Cell Biochem. 2017 May;118(5):1118-1131. doi: 10.1002/jcb.25729. Epub 2017 Jan 10.


Prostate cancer is the most common cancer in men and the second most common cause of cancer-related deaths in men. Although, various drugs targeting the androgen receptor are normally used, the patients frequently undergo recurrence of the disease. To overcome these limitations, natural compounds have been researched for evidence that they suppress progression and metastasis of various cancer cells. In the present study, we investigated effects of naringenin, a natural anti-oxidant flavonoid derived from citrus, on prostate cancer cells (PC3 and LNCaP). Results of present study with PC3 and LNCaP cells revealed that naringenin inhibited proliferation and migration, while inducing apoptosis and ROS production by those cells. In addition, naringenin-induced loss of mitochondrial membrane potential and increased Bax and decreased Bcl-2 proteins in PC3 cells, but not LNCaP cells. In a dose-dependent manner, naringenin decreased phosphorylation of ERK1/2, P70S6K, S6, and P38 in PC3 cells, and reduced phosphorylation of ERK1/2, P53, P38, and JNK proteins in LNCaP cells. However, naringenin activated phosphorylation of AKT in both PC3 and LNCaP cells. Then, targeted signaling proteins associated with viability of PC3 and LNCaP cells were analyzed using pharmacological inhibitors of AKT and ERK1/2 cell signaling pathways. Moreover, we compared the apoptotic effects of naringenin and paclitaxel alone and in combination to find that naringenin enhanced the efficiency of paclitaxel to suppress progression of prostate cancer cell lines. Collectively, these results indicate that naringenin is a potential chemotherapeutic agent for treatment of prostate cancer. J. Cell. Biochem. 118: 1118-1131, 2017. © 2016 Wiley Periodicals, Inc.


Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Flavanones / pharmacology*
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Paclitaxel / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Reactive Oxygen Species / metabolism


  • Antineoplastic Agents
  • Flavanones
  • Reactive Oxygen Species
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • naringenin
  • Paclitaxel