p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi

Abstract

Cancer cells exhibit hyperactive secretory states that maintain cancer cell viability and remodel the tumor microenvironment. However, the oncogenic signals that heighten secretion remain unclear. Here, we show that p53 loss activates prometastatic secretory vesicle biogenesis in the Golgi. p53 loss up-regulates the expression of a Golgi scaffolding protein, progestin and adipoQ receptor 11 (PAQR11), which recruits an adenosine diphosphate ribosylation factor 1–containing protein complex that loads cargos into secretory vesicles. PAQR11-dependent secretion of a protease, PLAU, prevents anoikis and initiates autocrine activation of a PLAU receptor/signal transducer and activator of transcription-3-dependent pathway that up-regulates PAQR11 expression, thereby completing a feedforward loop that amplifies prometastatic effector protein secretion. Pharmacologic inhibition of PLAU receptor impairs the growth and metastasis of p53-deficient cancers. Blockade of PAQR11-dependent secretion inhibits immunosuppressive processes in the tumor microenvironment. Thus, Golgi reprogramming by p53 loss is a key driver of hypersecretion in cancer.

Tumor Susceptibility Gene 101 (TSG101) Contributes to Virion Formation of Porcine Reproductive and Respiratory Syndrome Virus via Interaction with the Nucleocapsid (N) Protein along with the Early Secretory Pathway

“…ER and GA were extracted with the Minute ER/GA enrichment kit according to the manufacturer’s instructions ( 83 , 84 ). Briefly, for ER extraction, 3.0 × 10 7 cells were collected, frozen at −80°C for 10 min, and then resuspended in 550 μL of buffer A.…”

MMD scaffolds ACSL4 and MBOAT7 to promote polyunsaturated phospholipid synthesis and susceptibility to ferroptosis

“…MMD is a poorly studied Golgi-resident scaffold protein with no known enzymatic activity (Tan et al, 2017), and its known molecular functions had not previously been directly linked to ferroptosis sensitivity. We therefore explored a recently published proximity labeling interaction dataset that identified hundreds of potential interactors of MMD in H1299 human lung carcinoma cells (Tan et al, 2021). Strikingly, at the intersection of this dataset and the list of hits from both CRISPR screens was a single protein: the 79 kDa membrane-embedded isoform of acyl-CoA synthetase long-chain family member 4 (ACSL4), a PUFA-metabolizing enzyme with an established pro-ferroptotic function ( Figure 2A ) (Doll et al, 2017).…”

“…In addition to its identification in two screens, we noted that MMD expression positively correlates with sensitivity to established ferroptosis inducers across cancer cell lines, based on the Cancer Therapeutics Response Portal (Basu et al, 2013; Rees et al, 2016; Seashore-Ludlow et al, 2015). Moreover, MMD expression is elevated upon carcinoma cell epithelial-mesenchymal transition (EMT) and promotes metastatic outgrowth, a setting in which ferroptosis induction may offer therapeutic utility (Tan et al, 2021).…”

Tumor Suppressor Role of Wild-Type P53-Dependent Secretome and Its Proteomic Identification in PDAC

“…Upon various cancer therapy agents, the hepatic-activated p53 induces the secretion of proteins involved in hemostasis, immune response and cell adhesion [ 35 ]. Furthermore, p53 loss activates pro-tumorigenic secretory pathway and Golgi reprogramming is a driver of hypersecretion in cancer [ 36 , 37 , 38 ]. Thus, a loss of p53 has a profound impact on the secretome composition of cancer cells and marks the transition to invasiveness.…”