Activation of autophagy during farnesyl pyrophosphate synthase inhibition is mediated through PI3K/AKT/mTOR signaling. Issue 4 (October 2020)

• Record Type: Journal Article
• Authors: Han, Jie; Huang, Chaoyang; Jiang, Jiukun; Jiang, Dongmei
• Is Part Of: Journal of international medical research. Volume 48:Issue 4(2020)
• Publication Date: 2020-10
• Subjects: Autophagy -- HUVECs -- FPPS -- IBAN -- mTOR -- Atg7; Medicine -- Periodicals; Pharmacology -- Periodicals; 610.5
• DOI: 10.1177/0300060519875371
• Languages: English
• ISSNs: 0300-0605

Abstract

Objectives: Autophagy is divided into three phases: autophagosome engulfment of intracellular organelles and proteins, autophagosome fusion with lysosomes, and autolysosome degradation. The farnesyl pyrophosphate synthase inhibitor ibandronate (IBAN) has in vivo cardioprotective properties, potentially via anti-oxidant effects. Whether autophagy is involved in the cardioprotective effect of IBAN remains unexplored. Methods: Human umbilical vein endothelial cells (HUVECs) were treated in vitro with IBAN to assess autophagy induction. Lysosomal activation and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling were assessed using a LysoTracker assay, acridine orange staining and western blotting. An MTS assay was used to assess cellular proliferation. Autophagy was inhibited using chloroquine or RNA silencing of autophagy-related 7 (Atg7) expression. Results: IBAN induced autophagy in HUVECs. Moreover, IBAN activated lysosomal function, which is pivotal to autophagy induction. PI3K/AKT/mTOR activity was inhibited in IBAN-treated HUVECs, indicating the involvement of this pathway in IBAN-induced autophagy. Inhibition of autophagy using either chloroquine or Atg7 siRNA potentiated inhibition of HUVEC growth by IBAN, suggesting the involvement of non-autophagy pathways in the antiproliferative effects of IBAN. Conclusions: These findings provide insights into the role of autophagy in the cardioprotective effects of IBAN and the molecular mechanisms underlying autophagy induction by IBAN.