Regulation of Proapoptotic Mammalian ste20–Like Kinase MST2 by the IGF1-Akt Pathway

Hippo, a Drosophila serine/threonine kinase, promotes apoptosis and restricts cell growth and proliferation. Its mammalian homolog MST2 has been shown to play similar role and be regulated by Raf-1 via a kinase-independent mechanism and by RASSF family proteins through forming complex with MST2. However, regulation of MST2 by cell survival signal remains largely unknown.Using immunoblotting, in vitro kinase and in vivo labeling assays, we show that IGF1 inhibits MST2 cleavage and activation induced by DNA damage through the phosphatidylinosotol 3-kinase (PI3K)/Akt pathway. Akt phosphorylates a highly conserved threonine-117 residue of MST2 in vitro and in vivo, which leads to inhibition of MST2 cleavage, nuclear translocation, autophosphorylation-Thr180 and kinase activity. As a result, MST2 proapoptotic and growth arrest function was significantly reduced. Further, inverse correlation between pMST2-T117/pAkt and pMST2-T180 was observed in human breast tumors.Our findings demonstrate for the first time that extracellular cell survival signal IGF1 regulates MST2 and that Akt is a key upstream regulator of MST2

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance

Molecular Mechanism of AGC Kinases in Human Malignant

The maintenance of normal cell function and tissue homeostasis is dependent on the precise regulation of multiple signaling pathways that control cellular decisions to either proliferate, differentiate, arrest cell growth, or initiate programmed cell death (apoptosis). Cancer arises when clones of mutated cells escape this balance and proliferate inappropriately without compensatory apoptosis. Deregulated cell growth occurs as a result of perturbed signal transduction that modulates or alters cellular behavior or function to keep the critical balance between the rate of cell-cycle progression (cell division) and cell growth (cell mass) on one hand, and programmed cell death (apoptosis, autophagy) on the other. AGC kinases are activated downstream of a wide range of extracellular stimuli by distinct mechanisms. AGC kinase members such as Aurora-A and Akt regulate fundamental cellular functions including cell cycle, cell growth and survival. Inappropriate activation of those kinases has been associated with the development of diseases such as diabetes, autoimmunity, and cancer. The molecular mechanism of AGC kinases including Aurora-A and Akt involved in human cancers indicates that Aurora-A and Akt are important targets for cancer therapeutic strategies. We demonstrate, for the first time, that Aurora-A interacts with AR and phosphorylates AR at Thr282 and Ser293 in vitro and in vivo. Aurora-A induces AR transactivation activity in a phosphorylation-dependent manner. Ectopic expression Aurora-A in LNCaP cells induces the PSA expression and cell survival whereas knockdown of Aurora-A sensitizes LNCaP-RF cells to apoptosis and cell growth arrest. These data indicate that AR is a substrate of Aurora-A and that elevated Aurora-A could contribute to androgen-independent cell growth by phosphorylation and activation of AR. The NACHT leucine-rich repeat protein 1 (NALP1) is a member of the Ced-4 family and locates at chromosome 17p13.2 near TP53 locus. Here we demonstrated frequent somatic mutations and epigenetic silence of the NALP1 in human non-small cell lung, breast, ovarian and colon cancer. Restoration of NALP1 resulted in the inhibition of tumorigenic activity of the cell lines with NALP1 alterations. In addition to apoptosis, the cells expressing NALP1 largely undergo autophagy. Expression of NALP1 induces PI3KC3 kinase activity through directly interacts with Beclin 1, a protein required for activation of PI3KC3. Moreover, Akt phosphorylates NALP1 and disrupts the interaction between NALP1 and Beclin 1, leading to abrogation of NALP1-induced PI3KC3 activation and autophagy. Taken collectively, these data indicate that the NALP1 is a novel tumor suppressor gene on chromosome 17p13 and plays an important role in tumorigenesis by regulation of Beclin 1/PI3KC3 autophagic pathway and that Akt inhibits autophagy through regulation of NALP1/Beclin/ PI3KC3 cascade

IKBKE phosphorylation and inhibition of FOXO3a: a mechanism of IKBKE oncogenic function.

Forkhead box O (FOXO) transcription factors are emerging as key regulators of cell survival and growth. The transcriptional activity and subcellular localization of FOXO are tightly regulated by post-translational modifications. Here we report that IKBKE regulates FOXO3a through phosphorylation of FOXO3a-Ser644. The phosphorylation of FOXO3a resulted in its degradation and nuclear-cytoplasmic translocation. Previous studies have shown that IKBKE directly activates Akt and that Akt inhibits FOXO3a by phosphorylation of Ser32, Ser253 and Ser315. However, the activity of Akt-nonphosphorytable FOXO3a-A3 (i.e., converting 3 serine residues to alanine) was inhibited by IKBKE. Furthermore, overexpression of IKBKE correlates with elevated levels of pFOXO3a-S644 in primary lung and breast tumors. IKBKE inhibits cellular function of FOXO3a and FOXO3a-A3 but, to a much less extent, of FOXO3a-S644A. These findings suggest that IKBKE regulates FOXO3a primarily through phosphorylation of SerS644 and that IKBKE exerts its cellular function, at least to some extent, through regulation of FOXO3a

Potassium ferrous ferricyanide nanoparticles as a high capacity and ultralong life cathode material for nonaqueous potassium-ion batteries

We propose potassium ferrous ferricyanide (KFe II [Fe III (CN) 6 ]) nanoparticles with a 3D open framework structure as a cathode for nonaqueous K-ion batteries. Electrochemical reaction mechanism analyses identify that two redox-active sites based on C and N coordinated Fe II /Fe III redox couples play a role in K-ion storage, and no phase change occurs in the different states of the initial and second charge-discharge processes. Thus, the KFe II [Fe III (CN) 6 ] electrode exhibits a high discharge capacity of 118.7 mA h g -1 at an operating voltage of 3.34 V and extremely excellent cycling stability with a capacity value of 111.3 mA h g -1 after 100 cycles at 10 mA g -1 . Moreover, an ultralong cycling lifespan of 1000 cycles with a high capacity retention of 80.49% and extraordinary voltage stability at 100 mA g -1 can be acquired. Ex situ characterizations verify that the outstanding electrochemical performance of KFe II [Fe III (CN) 6 ] is attributed to superior structural stability and electrochemical reversibility upon long-term cycling. Therefore, the KFe II [Fe III (CN) 6 ] material can make KIBs competitive in EES applications

Chemical bonding boosts nano-rose-like MoS2 anchored on reduced graphene oxide for superior potassium-ion storage

The abundant and low-cost potassium resources promote potassium-ion batteries (KIBs) as promising energy storage devices, thus accelerating the investigation of ideal electrode materials to accommodate the large-size K-ions. Here, a nano-rose-like MoS2 confined in reduced graphene oxide (MoS2@rGO) is evaluated as anode material to boost K-ion storage. The MoS2@rGO hybrid not only features large specific surface area for excellent electron conductivity and facile K-ions diffusion, but also provides a robust three-dimension (3D) network with stable interfacial connection through strong chemical bonds (Mo-C and Mo-O-C) between MoS2 and rGO, which can alleviate the mechanical stress to guarantee the structure stability during cycling. It is also confirmed that both intercalation and conversion reaction mechanisms, based on four-electrons-transfer, play an important role in K-ions insertion/extraction. Hence, the initial capacity of 438.5 mAh·g−1 with excellent cycling stability (capacity retention of 95.0% after 200 cycles) at 100 mA g−1 and the remarkable rate capability (196.8 mAh·g−1 at 2 A g−1) among many reported anodes are achieved for MoS2@rGO. No obvious fading at 500 mA g−1 can be observed over ultra-long lifespan of 1000 cycles. Finally, the K-ion full cells are assembled with K2Fe[Fe(CN)6] cathode to demonstrate the practical application