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Published:
May 9, 2018DOI:
10.4314/tjpr.v17i3.3Keywords:
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Main Article Content
Inhibition of autophagy enhances SMI-4a-induced growth inhibition and apoptosis of melanoma cells
Abstract
Purpose: To investigate the exact role of the proviral integration site for Moloney murine leukemia virus-1 (PIM-1) on autophagy as well as the underlying molecular mechanisms in melanoma.
Methods: mRNA expression levels in A375 and G361 human melanoma cell lines were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Enzyme-linked immunosorbent (ELISA) and western blotting assays were applied to determine protein expression levels, while cell viability was evaluated using Cell Counting Kit 8 and colony formation assay. Flow cytometric analysis and caspase 3/7 activity assay were used to assess apoptosis.
Results: The results show that pharmacological inhibition of PIM-1 with its potent inhibitor (SMI-4a) suppressed cell viability and induced apoptosis in melanoma cell lines A375 and G361. SMI-4a also induced autophagy through inhibition of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) axis in melanoma cells. Furthermore, chloroquine, an inhibitor of autophagy, potentiated the SMI-4a-induced inhibition of tumour growth and promotion of apoptosis in melanoma cells in vitro and in vivo.
Conclusions: These results suggest that SMI-4a induces protective autophagy via PI3K/AKT/mTOR signaling pathway in melanoma cells. Thus, a combination of SMI-4a and an inhibitor of autophagy might be a novel approach to melanoma therapy.
Keywords: Apoptosis, Autophagy, Cell viability, Melanoma, PIM-1, SMI-4a
