Research Paper Volume 12, Issue 13 pp 13023—13037
The Gαh/phospholipase C-δ1 interaction promotes autophagosome degradation by activating the Akt/mTORC1 pathway in metastatic triple-negative breast cancer
- 1 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- 2 Department of Breast Surgery and General Surgery, Division of Surgery, Cardinal Tien Hospital, Xindian District, New Taipei, Taiwan
- 3 Department of Urology, Division of Surgery, Cardinal Tien Hospital, Xindian District, New Taipei, Taiwan
- 4 Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
- 5 Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- 6 Department of Neurology, Vertigo and Balance Impairment Center, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
- 7 Department of Otolaryngology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- 8 Department of Otolaryngology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
- 9 Department of Critical Care Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
- 10 Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
- 11 Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan
- 12 Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
- 13 Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
Received: December 3, 2019 Accepted: May 3, 2020 Published: July 1, 2020
https://doi.org/10.18632/aging.103390How to Cite
Copyright © 2020 Lin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Lung metastasis (LM) is commonly found in triple-negative breast cancer (TNBC); however, the molecular mechanism underlying TNBC metastasis to lungs remains largely unknown. We thus aimed to uncover a possible mechanism for the LM of TNBC. Here we show that the phosphorylation of Akt and mTORC1 was positively but the autophagy activity was negatively correlated with endogenous Gαh levels and cell invasion ability in TNBC cell lines. Whereas the knockdown of Gαh, as well as blocking its binding with PLC-δ1 by a synthetic peptide inhibitor, in the highly invasive MDA-MB231 cells dramatically suppressed Akt/mTORC1 phosphorylation and blocked autophagosome degradation, the overexpression of Gαh in the poorly invasive HCC1806 cells enhanced Akt/mTORC1 phosphorylation but promoted autophagosome degradation. The pharmaceutical inhibition of autophagy initiation by 3-methyladenine was found to rescue the cell invasion ability and LM potential of Gαh-silenced MDA-MB231 cells. In contrast, the inhibition of mTORC1 activity by rapamycin suppressed autophagosome degradation but mitigated the cell invasion ability and LM potential of Gαh-overexpressing HCC1806 cells. These findings demonstrate that the induction of autophagy activity or the inhibition of Akt-mTORC1 axis provides a useful strategy to combat the Gαh/PLC-δ1-driven LM of TNBC.
Abbreviations
TNBC: triple-negative breast cancer; ER: estrogen receptor; PLC-δ1: phospholipase C-δ1; GSEA: Gene set enrichment analysis; PPI: protein-protein interaction; RAPA: rapamycin; 3-MA: 3-methyladenine.