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Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
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Sorafenib induces renal cell carcinoma apoptosis via upregulating activating transcription factor 4

Qifei Wang, Guangzhen Wu, Xiangyu Che

    Die Pharmazie
    |March 17, 2018
    PubMed

    Insights

    Sorafenib suppresses renal cell carcinoma (RCC) viability by activating transcription factor 4 (ATF4). This activation triggers the ATF4-CHOP-PUMA pathway, leading to increased apoptosis in RCC cells.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Biochemistry

    Background:

    • Sorafenib is a multitargeted tyrosine kinase inhibitor used in various cancers.
    • The role of activating transcription factor 4 (ATF4) in sorafenib's efficacy for renal cell carcinoma (RCC) remains unexplored.

    Purpose of the Study:

    • To investigate the mechanism by which sorafenib impacts RCC, specifically focusing on the involvement of ATF4.
    • To determine if sorafenib-mediated ATF4 activation influences cell apoptosis and endoplasmic reticulum (ER) stress in RCC.

    Main Methods:

    • Sorafenib treatment on RCC cell lines (ACHN).
    • Assessment of cell viability, cell cycle, and apoptosis.
    • Analysis of ATF4, CCAAT/enhancer-binding protein-homologous protein (CHOP), and p53 upregulated modulator of apoptosis (PUMA) mRNA and protein levels.
    • Silencing of ATF4 using knockdown techniques.

    Main Results:

    • Sorafenib suppressed RCC cell viability in a time- and dose-dependent manner.
    • Sorafenib enhanced ATF4 mRNA and protein expression, inducing cell cycle arrest and apoptosis.
    • Sorafenib treatment increased CHOP and PUMA expression, contributing to apoptosis.
    • ATF4 knockdown partially reversed sorafenib-induced apoptosis and abolished CHOP/PUMA upregulation.

    Conclusions:

    • Sorafenib activates the ATF4-CHOP-PUMA pathway in RCC cells.
    • This pathway activation leads to enhanced ER stress and subsequent apoptosis in RCC.
    • ATF4 plays a crucial role in mediating sorafenib's anti-cancer effects in RCC.

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