BCL2L13 attenuation links impaired mitophagy to epithelial plasticity and anoikis tolerance in lung adenocarcinoma
BCL2L13 is a mitochondrial BCL2 family protein linked to mitophagy and ceramide metabolism, but its role in NSCLC metastatic plasticity remains unclear. Human lung cancer Tissue Microarray and matched patient specimens showed subtype and site dependent BCL2L13 expression, with higher cytoplasmic granular staining in primary NSCLC and reduced, heterogeneous staining in lymph node metastases, most…
BCL2L13, a mitochondrial BCL2 family protein, is associated with mitophagy and ceramide metabolism. Its role in non-small cell lung cancer (NSCLC) metastatic plasticity is not fully understood. In a study examining subtype and site-dependent BCL2L13 expression in human lung cancer tissue microarrays, higher cytoplasmic granular staining was observed in primary NSCLC, while reduced and heterogeneous staining was noted in lymph node metastases, particularly in adenocarcinoma and squamous cell carcinoma.
This primary-to-node attenuation suggested that BCL2L13 knockdown and overexpression could be tested in relevant NSCLC models.
In A549 and LLC cell lines, TGF-beta 1 induced coordinated mitophagy and epithelial-mesenchymal transition (EMT) with mitochondrial enrichment of BCL2L13. Knockdown of BCL2L13 impaired TGF-beta 1 and carbonyl cyanide m-chlorophenyl hydrazone-associated mitophagy, reducing LC3 beta colocalization with mitochondria, TOMM20, LAMP1 overlap, and mitochondrial LC3 II, p62 turnover, and shifting BNIP3 and NIX redistribution.
Loss of BCL2L13 enhanced EMT marker switching and migration, while overexpression partially counteracted these changes.
During detachment, BCL2L13 knockdown reduced anoikis-associated apoptosis despite preserved mitochondrial recruitment of BAX, BAK, BNIP3, NIX, altered BID processing, non-parallel caspase activity, and shifted FAK phosphorylation. Pharmacological autophagy modulation did not reverse this anoikis phenotype. Lipidomics identified adhesion state-dependent ceramide synthases CerS2 and CerS6 linked sphingolipid remodeling: BCL2L13 knockdown increased C24-linked sphingolipid species in attached cells but reduced C16 and C24 ceramide-related profiles during anoikis.
These results identify BCL2L13 downregulation as a metastasis-associated mitochondrial-lipid state that limits mitophagic quality control while promoting EMT and detachment survival in NSCLC adenocarcinoma.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
