BACKGROUND: Protein kinase D1 (PKD1) is a serine–threonine kinase that regulates various functions within the cell. Herein, we report the significance of PKD1 expression in glucose metabolism resulting in pancreatic cancer (PanCa) progression and chemo-resistance.
METHODS: PKD1 expression in PanCa was investigated by using immunohistochemistry. Functional and metabolic assays were utilised to analyse the effect of PKD1 expression/knockdown on associated cellular/molecular changes.
RESULTS: PKD1 expression was detected in human pancreatic intraepithelial neoplasia lesions (MCS=12.9; P < 0.0001) and pancreatic ductal adenocarcinoma samples (MCS=15, P < 0.0001) as compared with faint or no expression in normal pancreatic tissues (MCS= 1.54; P < 0.0001). Our results determine that PKD1 enhances glucose metabolism in PanCa cells, by triggering enhanced tumorigenesis and chemo-resistance. We demonstrate that mTORC1 activation by PKD1 regulates metabolic alterations in PanCa cells. siRNA knockdown of Raptor or treatment with rapamycin inhibited PKD1-accelerated lactate production as well as glucose consumption in cells, which confirms the association of mTORC1 with PKD1-induced metabolic alterations.
CONCLUSION: This study suggests a novel role of PKD1 as a key modulator of the glucose metabolism in PanCa cells accelerating tumorigenesis and chemo-resistance. The remodelling of PKD1-dysregulated glucose metabolism can be achieved by regulation of mTORC1 for development of novel therapeutic strategies.
Kumari, S., Khan, S., Sekhri, R., Mandil, H., Behrman, S., Yallapu, M. M., Chauhan, S. C., & Jaggi, M. (2020). Protein kinase D1 regulates metabolic switch in pancreatic cancer via modulation of mTORC1. British Journal of Cancer, 122(1), 121–131. https://doi.org/10.1038/s41416-019-0629-9
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British Journal of Cancer
Immunology and Microbiology