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2017 ; 9
(2
): 188-194
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Biological Effects of Hesperetin on Interleukin-6/Phosphorylated Signal
Transducer and Activator of Transcription 3 Pathway Signaling in Prostate Cancer
PC3 Cells
#MMPMID28539744
Shirzad M
; Heidarian E
; Beshkar P
; Gholami-Arjenaki M
Pharmacognosy Res
2017[Apr]; 9
(2
): 188-194
PMID28539744
show ga
BACKGROUND: Interleukin-6 (IL-6) is a multifunctional glycoprotein that regulates
the growth of some tumors, including prostate carcinomas due to signal transducer
and activator of transcription 3 (STAT3), extracellular signal-regulated kinases
1/2 (ERK1/2), and AKT signaling pathways. Hesperetin, as a flavanone, has several
biological properties such as antitumor and anti-inflammatory. OBJECTIVE: This
study was carried out to evaluate the biological effects of hesperetin on the
IL-6 gene expression and phosphorylated STAT3, AKT, and ERK1/2 signaling pathways
in PC3 prostate cancer (PC) cells. MATERIALS AND METHODS: In this study, we used
real-time quantitative polymerase chain reaction (RT-qPCR) and ELISA to evaluate
IL-6 gene expression and IL-6 protein secretion, respectively, in the treated PC3
cells with 0, 400, 450, and 500 ?M of hesperetin. Cell survival studies were done
by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay after 48 h
treatment with hesperetin, and cell apoptosis was determined by flow cytometry.
The protein levels of activated signaling molecules (pSTAT3, pAKT, and pERK1/2)
analyzed by immunoprecipitation technique. RESULTS: Hesperetin-treated PC3 cells
resulted in reduction of cell viability. Hesperetin led to the elevation of
phosphorylated STAT3, ERK1/2, and AKT signaling proteins after 48 h in a
dose-dependent manner as compared to the control cells. IL-6 gene expression, as
well as protein level, significantly increased (P < 0.05) in a dose-dependent
pattern in treated PC3 with hesperetin compared to the control cells. Further,
hesperetin exposure resulted in the induction of cell cycle arrest at G0/G1
phase. CONCLUSION: Hesperetin in PC3 cells led to elevation IL-6 gene expression,
IL-6 protein secretion, pSTAT3, pERK1/2 and pAKT intracellular signaling
proteins. Our results indicate that hesperetin treatment leads to the inhibition
of cell proliferation and the induction of cell cycle arrest at the G1 phase.
Hesperetin can be considered a potent agent which synchronizes and stops cell
cycle at G0/G1 phase to apply suitable chemotherapeutic agents and radiotherapy
in PC cells. SUMMARY: This study evaluates biological effects of hesperetin on
the cell cycle, interleukin-6 gene expression and some phosphorylated signaling
pathways in PC3 prostate cancer cells. Hesperetin resulted in the inhibition of
cell proliferation via inducing G0/G1 phase arrest in spite of the elevation of
interleukin-6 gene expression and phosphorylated AKT, STAT3, and ERK1/2
intracellular signaling proteins. Therefore, hesperetin can be considered a
potent agent which synchronizes and stop cell cycle at G0/G1 phase so that
suitable chemotherapeutic agents can be applied in PC3 prostate cancer cells.
Abbreviations Used: PC: Prostate cancer, IL-6: Interleukin-6, STAT3: Signal
transducer activator of transcription 3, ERK1/2: Extracellular signal-regulated
kinases 1/2, IC50: Inhibitory concentration of 50%.