Folliculin impairs breast tumor growth by repressing TFE3-dependent induction of the Warburg effect and angiogenesis

Non-canonical mTORC1 signaling at the lysosome

“…This is consistent with the results obtained in mice in which TFEB overexpression in specific tissues such as kidney and liver results in tumor formation [73,113]. In addition to TFEB/TFE3 translocations, increased expression and activities of MiT-TFE factors were identified as crucial contributors of tumor growth in PDAC, as well as in invasive basal-like breast carcinomas [60,114]. Thus, the aberrant activation of MiT-TFE factors may be implicated in a significantly larger number of malignancies than was initially expected (discussed in main text).…”

Phosphoproteomic Analysis of FLCN Inactivation Highlights Differential Kinase Pathways and Regulatory TFEB Phosphoserines

“…These three phosphoserine sites on TFEB were previously described to be dephosphorylated upon Torin-1 treatment or in response to oxidative stress by PP2A ( 19 ). Indeed, we found ROS levels significantly increased in our FLCN NEG RPTEC cells, a finding that is consistent with a recent observation in MCF7 cells ( 55 ). Furthermore, gene set enrichment analyses of our previous transcriptomic and proteomic study of FLCN NEG RPTEC cells revealed an enrichment of oxidative phosphorylation and ROS hallmark gene sets ( 8 ).…”

The Role of Decorin Proteoglycan in Mitophagy

“…While it is known that decorin activates AMPK for autophagic induction in endothelial cells, it is unknown whether decorin stimulates AMPK in a similar manner. This would be intriguing, especially in light of how AMPK functions in TNBC via the activity of folliculin (FLCK) [145]. Folliculin has been characterized as a tumor-suppressor protein and forms a regulatory complex with AMPK [146].…”

“…Folliculin has been characterized as a tumor-suppressor protein and forms a regulatory complex with AMPK [146]. The loss of FLCK results in the constitutive activation of AMPK, leading to enhanced engagement with PGC-1α, HIF-1α, and TFE3 to drive aggressive tumor formation and angiogenesis, particularly in TNBC [145]. Given this, decorin may finely regulate the interaction of FLCK with AMPK, and thus the output of AMPK signaling in TNBC to permit mitophagic activation and continued oncosuppression.…”