Sulforaphanes: disruptors of phagophores and autolysosomes

Abstract

Sulforaphane and its metabolites (SFNs) cause apoptosis in cancers and could be potential anti-cancer drugs. We focused on investigating the underlying mechanisms through which SFNs inhibit cancers. First, SFNs cause microtubule disruption by phosphorylated MAPK1/ERK2-MAPK3/ERK1-mediated activation of 26S proteasome leading to a microtubule-associated protein degradation and microtubule depolymerization. Second, SFNs cause the accumulation of autophagosomes and mitophagosomes via blocking their fusion with lysosomes. These changes might be involved in multiple signaling pathways. High-performance liquid chromatography-tandem mass spectrometry showed that SFN regulates the expression of lipoproteins; highly expressed FASN (fatty acid synthase) correlates with cancer malignancy and poor prognosis. More, SFN lowers the expressions of FASN, ACACA (acetyl-CoA carboxylase alpha), and ACLY (ATP citrate lyase) by activating the 26S proteasome; SFN inhibits the interactions of TUBA/α-tubulin with FASN, ACACA or ACLY; SFN also reduces the production of intracellular fatty acids; knockdown of FASN increases mitochondrial abnormality and apoptosis. Moreover, SFN decreases the expressions of mitophagy-associated proteins BNIP3L/NIX and BNIP3 and the interaction between BNIP3L/NIX and LC3-II/-I and upregulates mitochondria-associated LC3-II/-I. Therefore, SFN might cause apoptosis via inhibiting the microtubule-mediated lipoprotein activity and the fusion of lysosomes with autophagosomes and mitophagosomes.