The Gαh/phospholipase C-δ1 interaction promotes autophagosome degradation by activating the Akt/mTORC1 pathway in metastatic triple-negative breast cancer.

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.

• Authors: Hui-Yu Lin, Chia-Hao Kuei, Hsun-Hua Lee, Che-Hsuan Lin, Jing-Quan Zheng, Hui-Wen Chiu, Chi-Long Chen, Yuan-Feng Lin
• Journal: Aging (Aging (Albany NY)) Vol. 12 Issue 13 Pg. 13023-13037 (07 01 2020) ISSN: 1945-4589 [Electronic] United States
• PMID: 32615541 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Glutamine gamma Glutamyltransferase 2
• Transglutaminases
• Mechanistic Target of Rapamycin Complex 1
• Proto-Oncogene Proteins c-akt
• Phospholipase C delta
• GTP-Binding Proteins

Topics

• Autophagosomes (metabolism)
• Cell Line, Tumor
• Female
• GTP-Binding Proteins (genetics, metabolism)
• Gene Knockdown Techniques
• Humans
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Phospholipase C delta (metabolism)
• Phosphorylation
• Protein Glutamine gamma Glutamyltransferase 2
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (genetics)
• Transglutaminases (genetics, metabolism)
• Triple Negative Breast Neoplasms (genetics, metabolism)