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RECK has been described to modulate extracellular matrix components through negative regulation of MMP activities. Recently, RECK was demonstrated to bind to an orphan G protein‐coupled receptor GPR124 to mediate WNT7 signaling in nontumor contexts. Here, we attempted to clarify the role of RECK in driving WNT signaling in cancer cells. RECK and GPR124 formed a complex in 293T cells, and when both were expressed, WNT signaling was significantly enhanced in a WNT7‐dependent manner. This cooperation was abolished when RECK mutants unable to bind to GPR124 were transduced. RECK stimulated the growth of KRAS‐mutated pancreatic ductal adenocarcinoma (PDAC) cells with increased sensitivity to WNT inhibitor in a GPR124‐dependent manner. A gastric cancer cell line SH10TC endogenously expresses both RECK and GPR124 under regular culture conditions. In this cell line, inhibited cell growth and WNT signaling as well as increased apoptosis in the GPR124 depletion was dominantly found over those in the RECK deletion. These findings suggest that RECK promotes tumor cell growth by positively modulating WNT signaling through GPR124. This study proposes that the RECK/GPR124 complex might be a good therapeutic target in PDAC and gastric cancer. [ABSTRACT FROM AUTHOR]

Despite extensive efforts, oncogenic KRAS remains resistant to targeted therapy. Combined downstream RAL-TBK1 and MEK inhibition induces only transient lung tumor shrinkage in KRAS-driven genetically engineered mouse models (GEMMs). Using the sensitive KRAS;LKB1 (KL) mutant background, we identify YAP1 upregulation and a therapy-induced secretome as mediators of acquired resistance. This program is reversible, associated with H3K27 promoter acetylation, and suppressed by BET inhibition, resensitizing resistant KL cells to TBK1/MEK inhibition. Constitutive YAP1 signaling promotes intrinsic resistance in KRAS;TP53 (KP) mutant lung cancer. Intermittent treatment with the BET inhibitor JQ1 thus overcomes resistance to combined pathway inhibition in KL and KP GEMMs. Using potent and selective TBK1 and BET inhibitors we further develop an effective therapeutic strategy with potential translatability to the clinic.

Simple Summary: There have been several reports that progression-free survival in patients with unresectable pancreatic neuroendocrine neoplasms (panNENs) could be improved by an antidiabetic drug, metformin. In this study, we evaluated the effects of metformin on cell metabolism and viability using the panNEN cell line, QGP-1, and RIN-m. We are the first to show that the administration of metformin to QGP-1 and RIN-m activates adenosine monophosphate-activated protein kinase and suppresses mitochondrial respiration using an XF analyzer. The impact of this study is to elucidate how metformin has an antitumor effect against panNEN. Although pancreatic neuroendocrine neoplasms (panNENs) are much less common and have a better prognosis than exocrine pancreatic cancers, their recurrence rate is not low, even in Grade 1 (World Health Organization classification) panNEN. Recently, there have been several reports that the progression-free survival in patients with unresectable panNEN could be improved by an antidiabetic drug, metformin, with the co-treatment of everolimus or a somatostatin analog. In this study, we aimed to evaluate the effects of metformin on cell metabolism and viability using the panNEN cell line, QGP-1, and RIN-m in culture. We observed an inhibitory effect of metformin on QGP-1 cell proliferation in a dose-dependent manner. Metformin was found to decrease the oxygen consumption rate in QGP-1 and RIN-m cells after metformin 48 h treatment and immediately after exposure. Cell proliferation was suppressed after metformin treatment. Phosphorylated adenosine monophosphate-activated protein kinase (AMPK) expression was increased, and cyclin D1 expression was decreased in RIN-m cells 24 h after metformin treatment by Western blotting in a dose-dependent manner. In conclusion, suppressive mitochondrial respiration and AMPK activation by metformin are, thus, suggested to inhibit panNEN cell viability and cell survival. [ABSTRACT FROM AUTHOR]

Chemists have long sought to regulate the reactivity of H2, to yield hydride ions, hydrogen atoms, or electrons on demand. One source of inspiration for achieving this control is [NiFe]hydrogenase ([NiFe]H2ase), which reacts with H2 to form various hydrogen active species such as NiIII hydride species, NiII hydride species, and NiI low‐valent species. Chemists have attempted to synthesize these hydrogen active species not only as models for the active species of [NiFe]H2ase, but also as electron transfer catalysts. However, the synthesis of NiI complex directly from H2 has not been reported. This paper reports the first example of a single‐step synthesis of a NiI complex, via reaction of a NiII complex with H2, stable for over 3 months at room temperature and we further demonstrate a reductive coupling of acridinium ions as part of a reaction cycle. [ABSTRACT FROM AUTHOR]

Chemists have long sought to regulate the reactivity of H2, to yield hydride ions, hydrogen atoms, or electrons on demand. One source of inspiration for achieving this control is [NiFe]hydrogenase ([NiFe]H2ase), which reacts with H2 to form various hydrogen active species such as NiIII hydride species, NiII hydride species, and NiI low‐valent species. Chemists have attempted to synthesize these hydrogen active species not only as models for the active species of [NiFe]H2ase, but also as electron transfer catalysts. However, the synthesis of NiI complex directly from H2 has not been reported. This paper reports the first example of a single‐step synthesis of a NiI complex, via reaction of a NiII complex with H2, stable for over 3 months at room temperature and we further demonstrate a reductive coupling of acridinium ions as part of a reaction cycle. [ABSTRACT FROM AUTHOR]