Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 Signaling

Abstract

Lung adenocarcinoma (LADC), the most common type of lung cancer, is still one of the most aggressive and rapidly fatal tumor types, even though achievements in new therapeutic approaches have been developed. Elaiophylin as a C2 symmetrically glycosylated 16 macrolides has been reported to be a late-stage autophagy inhibitor with a potent anti-tumor effect on various cancers. This study investigated the anti-tumor effect of elaiophylin on human LADC for the first time in in vitro and in vivo models. The in vitro study in LADC A549 cells showed that elaiophylin significantly inhibited cell viability and induced cell apoptosis through the suppression of mitophagy and induction of cellular and mitochondrial oxidative stress. Proteomic analysis and molecular docking assay implicated that SIRT1 was likely the direct target of elaiophylin in A549 cells. Further mechanistic study verified that elaiophylin reduced Nrf2 deacetylation, expression, and transcriptional activity as well as cytoplasm translocation by downregulating SIRT1 expression and deacetylase activity. Additionally, SIRT1/Nrf2 activation could attenuate elaiophylin-induced mitophagy inhibition and oxidative stress. The in vivo study in the A549-xenograft mice model showed that the anti-tumor effect of elaiophylin was accompanied by the decreased expressions of SIRT1, Nrf2, Parkin, and PINK1. Thus, the present study reports that elaiophylin has potent anti-tumor properties in LADC, which effect is likely mediated through suppressing the SIRT1/Nrf2 signaling. In conclusion, elaiophylin may be a novel drug candidate for LADC and SIRT1 may be a new therapeutic target for such devastating malignancy.

Elaiophylin Elicits Robust Anti-Tumor Responses via Apoptosis Induction and Attenuation of Proliferation, Migration, Invasion, and Angiogenesis in Pancreatic Cancer Cells

“…Further investigations are imperative to delineate the differential molecular mechanisms activated in cancerous versus normal cells in response to elaiophylin. This observation also emphasizes the necessity for careful dosage considerations when contemplating elaiophylin as a therapeutic agent for pancreatic cancer, given its potential effects on normal cells at therapeutic concentrations [13,[22][23][24]. In addition, the colony-formation assay further supported the idea that elaiophylin-treated cells formed fewer and smaller colonies compared to the control group.…”

“…In this regard, our study offers a comprehensive evaluation of the potential therapeutic effects of elaiophylin, a macrolide antibiotic derived from Streptomyces melanosporus, in pancreatic cancer treatment. Emerging evidence from various cancer cell lines suggests that elaiophylin exerts anti-tumor effects through mechanisms such as inhibiting autophagy/mitophagy [22], triggering paraptosis [13], inducing oxidative stress [23], suppressing angiogenesis [24], and activating endoplasmic reticulum (ER) stress [25]. Key pathways implicated include the inhibition of SIRT1/Nrf2 signaling, MAPK hyperactivation, downregulation of VEGF, and inhibition of SIRT1/FoxO3a signaling.…”