Cancer Metabolism

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

Abstract

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.

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Acknowledgements

The authors are thankful to Dr. Manish Tripathi, UTHSC for his assistance in analysing available datasets for PKD1 expression in PDAC.

Author contributions

S.K. (first author) performed most of the experiments, acquired and analysed the data. S.K. (second author) supervised the project, helped the author in the paper writing and critically reviewed the results. S.C.C. and M.J. supervised the project and critically reviewed the paper. S.B. provided a clinical insight in the studies, and M.M.Y. reviewed the whole paper. R.S. analysed the immunohistochemistry results, and H.M. performed the immunohistochemistry of PKD1.

Author information

Correspondence to Sheema Khan or Meena Jaggi.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Archived human specimens were collected under the Institutional Review Board of University of Tennessee Health Science Center (13-02690-XM) and Baptist Memorial Hospital (BMH), Memphis (BMH-IRB WOA 14-05). The study was performed in accordance with the Declaration of Helsinki. This study involved the use of only archived tissues, so the informed consent to participate from the subjects was not required and is waived by the ethics board.

Funding

This work was partially supported by grants from the National Institutes of Health (R01 CA206069, CA204552 and CA210192 to S.C.C. and M.J.), and the College of Pharmacy 2017 and 2018 Dean’s Seed/Instrument/New support grants of the University of Tennessee Health Science Center (to S.C.C., M.J. and S.K.). We acknowledge the financial support of Herb Kosten Foundation and generous donation from Dermon family.

Consent to publish

Not applicable.

Data availability

The data sets analysed during this study are available from the corresponding author on reasonable request.

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Kumari, S., Khan, S., Sekhri, R. et al. Protein kinase D1 regulates metabolic switch in pancreatic cancer via modulation of mTORC1. Br J Cancer 122, 121–131 (2020). https://doi.org/10.1038/s41416-019-0629-9

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