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CHLOROQUINE DOES NOT CANCEL E1A+cHa-Ras TRANSFORMANTS’ DEATH INDUCED BY mTOR KINASE INHIBITOR pp242.

T V Bykova, S G Zubova,, E Yu Kochetkova

    Tsitologiia
    |September 7, 2018
    PubMed

    Insights

    Combining chloroquine and pp242 effectively induces cell death in Ras-transformed fibroblasts. This combination targets both intact and senescent cells by inhibiting autophagy and mitochondrial function.

    Area of Science:

    • Cell Biology
    • Biochemistry
    • Oncology

    Background:

    • Cellular senescence and autophagy are critical processes in aging and cancer.
    • Ras-transformed cells exhibit altered metabolic and survival pathways.
    • Understanding the interplay between autophagy and cell death is crucial for therapeutic development.

    Purpose of the Study:

    • To investigate the impact of autophagy modulation on cell viability in control and senescent Ras-transformed rat embryo fibroblasts.
    • To evaluate the efficacy of pp242, a TORC1/C2 kinase inhibitor, in inducing cell death via autophagy.
    • To determine the combined effect of pp242 and chloroquine (a lysosomal inhibitor) on cell viability.

    Main Methods:

    • Induction of cell senescence using sodium butyrate.
    • Treatment of fibroblasts with pp242 to trigger autophagy.
    • Assessment of cell viability and mitochondrial function.
    • Inhibition of lysosome-autophagosome fusion using chloroquine.

    Main Results:

    • pp242 significantly reduced mitochondrial activity and induced cell death through mitophagy and apoptosis in intact cells.
    • Senescent cells showed greater resistance to pp242 compared to control cells.
    • The combination of chloroquine and pp242 markedly reduced the viability of both intact and senescent Ras-transformed cells.
    • Chloroquine did not abolish the effects of pp242, suggesting complex autophagic regulation.

    Conclusions:

    • The combination of chloroquine and pp242 represents a potent strategy for inducing cell death in Ras-transformed cells.
    • This therapeutic approach is effective in both non-senescent and senescent transformed cells.
    • Targeting autophagy and mitochondrial pathways offers a promising avenue for cancer therapy.

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