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Quercetin regulates insulin like growth factor signaling and induces intrinsic and extrinsic pathway mediated apoptosis in androgen independent prostate cancer cells (PC-3)

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Abstract

Progression of prostate cancer is facilitated by growth factors that activate critical signaling cascades thereby promote prostate cancer cell growth, survival, and migration. To investigate the effect of quercetin on insulin-like growth factor signaling and apoptosis in androgen independent prostate cancer cells (PC-3), IGF-IR, PI-3K, p-Akt, Akt, cyclin D1, Bad, cytochrome c, PARP, caspases-9 and 10 protein levels were assessed by western blot analysis. Mitochondrial membrane potency was detected by rhodamine-123 staining. Quercetin induced caspase-3 activity assay was performed for activation of apoptosis. Further, RT-PCR was also performed for Bad, IGF-I, II, IR, and IGFBP-3 mRNA expression. Quercetin significantly increases the proapoptotic mRNA levels of Bad, IGFBP-3 and protein levels of Bad, cytochrome C, cleaved caspase-9, caspase-10, cleaved PARP and caspase-3 activity in PC-3 cells. IGF-IRβ, PI3K, p-Akt, and cyclin D1 protein expression and mRNA levels of IGF-I, II and IGF-IR were decreased significantly. Further, treatment with PI3K inhibitor (LY294002) and quercetin showed decreased p-Akt levels. Apoptosis is confirmed by loss of mitochondrial membrane potential in quercetin treated PC-3 cells. This study suggests that quercetin decreases the survival of androgen independent prostate cancer cells by modulating the expression of insulin-like growth factors (IGF) system components, signaling molecules and induces apoptosis, which could be very useful for the androgen independent prostate cancer treatment.

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Abbreviations

IGF:

Insulin-like growth factor

IGF-IR:

IGF type I receptor

IGFBPs:

IGFs binding proteins

PI-3K:

Phosphatidyl inositol-3 kinase

ERK:

Extracellular regulated kinase

Akt:

Protein kinase B

Bad:

Bcl-2-associated domain

PARP:

Poly (ADP)-ribose polymerase

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Acknowledgment

The financial support from Council for scientific and Industrial research in the form of senior research fellowship (CSIR-SRF) is greatly acknowledged.

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Authors and Affiliations

  1. Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai, 600113, Tamilnadu, India

    Kalimuthu Senthilkumar, Perumal Elumalai, Ramachandran Arunkumar, Sivanantham Banudevi, Nandagopal Dharmalingam Gunadharini, Govindaraj Sharmila, Kandaswamy Selvakumar & Jagadeesan Arunakaran

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  1. Kalimuthu Senthilkumar
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  2. Perumal Elumalai
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  3. Ramachandran Arunkumar
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Correspondence to Jagadeesan Arunakaran.

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Senthilkumar, K., Elumalai, P., Arunkumar, R. et al. Quercetin regulates insulin like growth factor signaling and induces intrinsic and extrinsic pathway mediated apoptosis in androgen independent prostate cancer cells (PC-3). Mol Cell Biochem 344, 173–184 (2010). https://doi.org/10.1007/s11010-010-0540-4

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