FANCL supports Parkin-mediated mitophagy in a ubiquitin ligase-independent manner.

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. The FA proteins have functions in genome maintenance and in the cytoplasmic process of selective autophagy, beyond their canonical roles of repairing DNA interstrand cross-links. FA core complex proteins FANCC, FANCF, FANCL, FANCA, FANCD2, BRCA1 and BRCA2, which previously had no known direct functions outside the nucleus, have recently been implicated in mitophagy. Although mutations in FANCL account for only a very small number of cases in FA families, it plays a key role in the FA pathophysiology and might drive carcinogenesis. Here, we demonstrate that FANCL protein is present in mitochondria in the control and Oligomycin and Antimycin (OA)-treated cells and its ubiquitin ligase activity is not required for its localization to mitochondria. CRISPR/Cas9-mediated knockout of FANCL in HeLa cells overexpressing parkin results in increased sensitivity to mitochondrial stress and defective clearing of damaged mitochondria upon OA treatment. This defect was reversed by the reintroduction of either wild-type FANCL or FANCL(C307A), a mutant lacking ubiquitin ligase activity. To summarize, FANCL protects from mitochondrial stress and supports Parkin-mediated mitophagy in a ubiquitin ligase-independent manner.

Andrographolide as a Therapeutic Agent Against Breast and Ovarian Cancers.

Andrographolide (ANDR), isolated from Andrographis paniculata, is a medicinal compound effective against infections, inflammatory disorders, and various cancers. In the present study, the effects of ANDR on NFkB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation, caspase-8-mediated apoptosis and pyroptosis, and extra cellular matrix (ECM) degradation were analyzed in A431, MDA-MB231, and SKOV-3 cell lines. Results showed that ANDR inhibited the growth and proliferation of cancer cell lines by inhibiting NFkB signaling. A significant decrease in phospho-p65 level was observed upon increasing ANDR concentration in epidermoid carcinoma and breast cancer cell lines, A431 and MDA-MB231, respectively. Accordingly, upon ANDR treatment, the expression of caspase-8 was increased, whereas no significant induction of caspase-1 expression was observed. Moreover, we observed a significant increase in the expression of tissue inhibitor of metallopeptidase-1 (TIMP1) upon increasing ANDR concentration. Such induction of TIMP1 inhibited the activity of matrix metallopeptidase-7 (MMP-7), thus preventing the degradation of ECM. Therefore, as ANDR shows cytotoxicity towards cancer cells via the NFkB signal transduction pathway without inducing pyroptosis and blocks breast and ovarian cancer invasion by inhibiting MMP-7 expression through TIMP1 up-regulation, it has the potential to be developed as a drug targeting ovarian and breast cancers.