Cellular senescence is an initial barrier for carcinogenesis. However, the signaling mechanisms that trigger cellular senescence are incompletely understood, particularly in vivo. Here we identify Wnt7a as a novel upstream inducer of cellular senescence. In two different mouse strains (C57Bl/6J and FVB/NJ), we show that the loss of Wnt7a is a major contributing factor for increased lung tumorigenesis owing to reduced cellular senescence, and not reduced apoptosis, or autophagy. Wnt7a-null mice under de novo conditions and in both the strains display E-cadherin-to-N-cadherin switch, reduced expression of cellular senescence markers and reduced expression of senescence-associated secretory phenotype, indicating a genetic predisposition of these mice to increased carcinogen-induced lung tumorigenesis. Interestingly, Wnt7a induced an alternate senescence pathway, which was independent of β-catenin, and distinct from that of classical oncogene-induced senescence mediated by the well-known p16INK4a and p19ARF pathways. Mechanistically, Wnt7a induced cellular senescence via inactivation of S-phase kinase-associated protein 2, an important alternate regulator of cellular senescence. Additionally, we identified Iloprost, a prostacyclin analog, which initiates downstream signaling cascades similar to that of Wnt7a, as a novel inducer of cellular senescence, presenting potential future clinical translational strategies. Thus pro-senescence therapies using either Wnt7a or its mimic, Iloprost, might represent a new class of therapeutic treatments for lung cancer.
Background Growth arrest-specific protein 6 signals through the TAM (TYRO-3-AXL-MERTK) receptor family, mediating platelet activation and thrombus formation via activation of the aggregate-stabilizing α β integrin. Objective To describe the antithrombotic effects mediated by UNC2025, a small-molecule MERTK tyrosine kinase inhibitor. Methods MERTK phosphorylation and downstream signaling were assessed by immunoblotting. Light transmission aggregometry, flow cytometry and microfluidic analysis were used to evaluate the impact of MERTK inhibition on platelet activation and stability of aggregates in vitro. The effects of MERTK inhibition on arterial and venous thrombosis, platelet accumulation at microvascular injury sites and tail bleeding times were determined with murine models. The effects of combined treatment with ADP-P2Y pathway antagonists and UNC2025 were also evaluated. Results and Conclusions Treatment with UNC2025 inhibited MERTK phosphorylation and downstream activation of AKT and SRC, decreased platelet activation, and protected animals from pulmonary embolism and arterial thrombosis without increasing bleeding times. The antiplatelet effect of UNC2025 was enhanced in combination with ADP-P2Y pathway antagonists, and a greater than additive effect was observed when these two agents with different mechanisms of inhibition were coadministered. TAM kinase signaling represents a potential therapeutic target, as inhibition of this axis, especially in combination with ADP-P2Y pathway antagonism, mediates decreased platelet activation, aggregate stability, and thrombus formation, with less hemorrhagic potential than current treatment strategies. The data presented here also demonstrate antithrombotic activity mediated by UNC2025, a novel translational agent, and support the development of TAM kinase inhibitors for clinical applications.
SummaryIn non-small cell lung cancer cell lines, activation of β-catenin independent signaling, via Wnt7a/Frizzled9 signaling, leads to reversal of cellular transformation, reduced anchorage-independent growth and induction of epithelial differentiation. miRNA expression profiling on a human lung adenocarcinoma cell line (A549) identified hsa-miR29b as an important downstream target of Wnt7a/Frizzled9 signaling. We show herein that hsa-miR29b expression is lost in non-small cell lung cancer (NSCLC) cell lines and stimulation of β-catenin independent signaling, via Wnt7a expression, in NSCLC cell lines results in increased expression of hsa-miR29b. Surprisingly, we also identify specific regulation of hsa-miR29b by Wnt7a but not by Wnt3, a ligand for β-catenin-dependent signaling. Interestingly, knockdown of hsa-miR29b was enough to abrogate the tumor suppressive effects of Wnt7a/Frizzled9 signaling in NSCLC cells, suggesting that hsa-miR29b is an important mediator of β-catenin independent signaling. Finally, we show for the first time that hsa-miR29b plays an important role as a tumor suppressor in lung cancer by targeting murine double mutant 2 (MDM2), revealing novel nodes for Wnt7a/Frizzled9-mediated regulation of NSCLC cell proliferation.
Targeted therapies for cancer bring the hope of specific treatment, providing high efficacy and in some cases lower toxicity than conventional treatment. Although targeted therapeutics have helped immensely in the treatment of several cancers, like chronic myelogenous leukemia, colon cancer, and breast cancer, the benefit of these agents in the treatment of lung cancer remains limited, in part due to the development of drug resistance. In this review, we discuss the mechanisms of drug resistance and the current strategies used to treat lung cancer. A better understanding of these drug-resistance mechanisms could potentially benefit from the development of a more robust personalized medicine approach for the treatment of lung cancer.
The authors wish to make readers aware of a typographical error in the above paper for the amount of urethane administered to the Wnt7a mice. The amount given should read as 1 mg/g body weight not 1 mg/kg body weight.In the Results section in page 4, the following paragraph should be amended to read:To test this idea, we probed for the effects of urethane (ethyl carbamate)-induced lung tumor formation in wild type and Wnt7a-null mice, a prototypical model to study lung tumorigenesis. [26][27][28] Urethane is a chemical carcinogen, which causes activating mutations in K-Ras, 27,28 leading to the formation of lung tumors in mice. Several studies have highlighted a strainspecific response to urethane; for example, FVB/NJ strains are susceptible to lung tumorigenesis, whereas C57Bl/6J, in contrast, are more resistant. [26][27][28] Therefore, in our studies, wild type and Wnt7a null in FVB/NJ mice received the standard single dose of 1 mg/g body weight of urethane, whereas wild type and Wnt7a null in C57Bl/6J mice received weekly injections of 1 mg/g body weight of urethane for 6 weeks. The mice were euthanized and dissected after 20 weeks (FVB/NJ strains) or 40 weeks (C57Bl/6J strains) to assess the formation of lung tumors.In the Materials and Methods section on page 10, the following paragraph should be amended to read:Urethane treatment. Six-to-eight-week-old mice were given intraperitoneal injections of either 0.9% saline or urethane (1 mg/g body weight). Wild-type and Wnt7a-null mice in FVB/NJ strain received the standard single dose of urethane, whereas the wild-type and Wnt7a-null mice in C57Bl/6J strain received weekly injections of 1 mg/g body weight of urethane for 6 weeks. The control and experimental mice were weighed weekly to observe any changes in body weight until they were euthanized. The mice were euthanized and dissected after 20 weeks (FVB/NJ strains) or 40 weeks (C57Bl/6J strains) to assess the formation of lung tumors. Lung tumors were counted and measured using digital calipers (Fisher Scientific, Waltham, MA, USA).The authors apologise for any inconvenience caused by this error.This error has now been rectified, and the corrected article appears in this issue. The html and online pdf versions have also been rectified, and now carry the corrected paper.
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