Plasminogen activator urokinase expression reveals TRAIL responsiveness and supports fractional survival of cancer cells

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/TNFSF10/Apo2L) holds promise for cancer therapy as it induces apoptosis in a large variety of cancer cells while exerting negligible toxicity in normal ones. However, TRAIL can also induce proliferative and migratory signaling in cancer cells resistant to apoptosis induced by this cytokine. In that regard, the molecular mechanisms underlying the tumor selectivity of TRAIL and those balancing apoptosis versus survival remain largely elusive. We show here that high mRNA levels of PLAU, which encodes urokinase plasminogen activator (uPA), are characteristic of cancer cells with functional TRAIL signaling. Notably, decreasing uPA levels sensitized cancer cells to TRAIL, leading to markedly increased apoptosis. Mechanistic analyses revealed three molecular events taking place in uPA-depleted cells: reduced basal ERK1/2 prosurvival signaling, decreased preligand decoy receptor 2 (DcR2)-death receptor 5 (DR5) interaction and attenuated recruitment of DcR2 to the death-inducing signaling complex upon TRAIL challenge. These phenomena were accompanied by increased FADD and procaspase-8 recruitment and processing, thus guiding cells toward a caspase-dependent cell death that is largely independent of the intrinsic apoptosis pathway. Collectively, our results unveil PLAU mRNA levels as marker for the identification of TRAIL-responsive tumor cells and highlight a key role of uPA signaling in ‘apoptosis versus survival' decision-making processes upon TRAIL challenge.

Surviving apoptosis: life–death signaling in single cells

“…For example, cells have been shown to switch between drug-sensitive and drug-resistant states, or to develop resistance following a drug treatment and then become sensitive again when given a “drug holiday” 91–95 . Dynamic TRAIL-resistance has similarly been observed in several studies, and has been collectively attributed to changes at the level of receptors, DISC, or Bcl-2 family proteins 40,56,96–98 . In some of these cases, cells in a population may pre-exist in a dynamic equilibrium of sensitive and resistant states and switch back and forth over time, whereas in other cases, reversible resistance in a fraction of cells results from a drug-induced adaptive state 90–95,99–101 .…”

Proteomic Analysis of the Secretome of Porcine Alveolar Macrophages Infected with Porcine Reproductive and Respiratory Syndrome Virus

“…Notably, the proteins involved in positive regulation of apoptosis, such as BCL2L13, which is a member of the Bcl‐2 family with pro‐apoptotic activity, and GCLC, which is a direct target of caspase‐mediated cleavage in multiple models of apoptotic cell death, were down‐regulated in PRRSV‐infected cell supernatants. However, proteins involved in the negative regulation of apoptosis, such as PLAUR, which regulates cell survival and is important for VEGF‐induced anti‐apoptosis, and OPA1, which is located on the inner mitochondrial membrane and protects cells from apoptosis by preventing the release of cytochrome c from the mitochondria, were up‐regulated in the supernatant of PRRSV‐infected cells. These data reflect a down‐regulation in apoptosis of PRRSV‐infected cells.…”

“…Notably, several proteins involved in the positive regulation of the apoptosis process, such as glutamate cysteine ligase catalytic subunit (GCLC), [29] Bcl-2-like protein 13 (BCL2L13), [30] and Cbl proto-oncogene-E3 ubiquitin protein ligase (CBL), [31] were significantly down-regulated in the PRRSV-infected cell supernatants, as compared with the mock-infected cell supernatants. In addition, 14-3-3 sigma protein, [32] plasminogen activator-urokinase receptor (PLAUR), [33] and dynamin-like 120 kDa proteinmitochondrial (OPA1), [34] which contribute to the negative regulation of the apoptotic process, were significantly up-regulated in the PRRSV-infected cell supernatants, as compared with the mock-infected cell supernatants. PRRSV utilizes the host transcription and translation systems to complete its replication.…”

MiR-34a suppresses amphiregulin and tumor metastatic potential of head and neck squamous cell carcinoma (HNSCC)

“…For decades, the urokinase plasminogen activator (uPA) system has been thought to drive tumor progression by mediating directed extracellular proteolysis on the surface of migrating or invading cells. Intervention with this proteolysis by targeting uPA system has been proposed to represent a novel approach for inhibiting tumor progression and a potential value as molecular prognostic marker prostate cancer, melanoma, breast cancer, pancreatic cancer, gastric cancer, thyroid cancer, and etc [ 54 – 58 ]. Previous researches also showed that the downstream factors of ErbB pathway, such as MMP-9, uPA, EMMPRIN, and PAI-1, could be induced by AREG in head and neck cancer [ 28 , 29 ], breast cancer [ 59 , 60 ], and malignant mesothelioma cell lines [ 61 ].…”