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.

A Multidisciplinary Approach Establishes a Link between Transglutaminase 2 and the Kv10.1 Voltage-Dependent K+ Channel in Breast Cancer

“…It might be important to underline also that the binding of PLCδ1 by TG2 supports autophagosome degradation in MDA-MB-231 cells [90]; therefore, blocking the formation of this complex could have therapeutic implications.…”

Endorsement of TNBC Biomarkers in Precision Therapy by Nanotechnology

“…BKM120, the PI3K inhibitor, exhibited a significant inhibition of tumor growth, with 84% tumor-growth inhibition [123]. Lin et al, 2020 used rapamycin, an inhibitor of mTORC1, to treat metastatic TNBC [124]. In phase II clinical trials (NCT02162719), TNBC patients received paclitaxel i.v.…”

Targeted Therapeutic Strategies for Triple-Negative Breast Cancer

“…It has been shown that BKM120 therapy led to significant tumor growth inhibition in all models, with the percentage of tumor growth inhibition (%TGI) ranging from 35% in the least sensitive model WHIM12 (PTEN-deficient) and 84% in the most sensitive model WHIM4 (PTEN-normal) (22). Lin et al proposed another strategy for using an mTORC1 inhibitor, rapamycin, to combat metastatic TNBC with upregulated Gah, also known as tissue transglutaminase (tTG) or transglutaminase 2 (TG2) (23). Patients from a randomized, double-blind, phase II trial (NCT02162719) received intravenous paclitaxel with or without Akt inhibitor ipatasertib until disease progression or unacceptable toxicity.…”