Protein kinase D1 regulates metabolic switch in pancreatic cancer via modulation of mTORC1.

Published on Jan 1, 2020in British Journal of Cancer5.791
· DOI :10.1038/S41416-019-0629-9
Sonam Kumari8
Estimated H-index: 8
(UTHSC: University of Tennessee Health Science Center),
Sheema Khan1
Estimated H-index: 1
(University of Texas at Austin)
+ 5 AuthorsMeena Jaggi36
Estimated H-index: 36
(University of Texas at Austin)
Sources
Abstract
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. 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. 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. 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.
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