Detergent-insoluble inclusion constitutes the first pathology in PFN1 transgenic rats.

Mutation of profilin 1 (PFN1) can cause amyotrophic lateral sclerosis (ALS). To assess how PFN1 mutation causes the disease, we created transgenic rats with human genomic DNA that harbors both the coding and the regulatory sequences of the human PFN1 gene. Selected transgenic lines expressed human PFN1 with or without the pathogenic mutation C71G at a moderate and a comparable level and in the similar pattern of spatial and temporal expression to rat endogenous PFN1. The artificial effects of arbitrary transgene expression commonly observed in cDNA transgenic animals were minimized in PFN1 transgenic rats. Expression of the mutant, but not the wild type, human PFN1 in rats recapitulated the cardinal features of ALS including the progressive loss of motor neurons and the subsequent denervation atrophy of skeletal muscles. Detergent-insoluble PFN1 inclusions were detected as the first pathology in otherwise asymptomatic transgenic rats expressing mutant human PFN1. The findings suggest that protein aggregation is involved in the neurodegeneration of ALS associated with PFN1 mutation. The resulting rat model is useful to mechanistic study on the ALS.

Controllable CO2-responsiveness of O/W emulsions by varying the alkane carbon number of a tertiary amine.

A series of CO2-responsive oil-in-water (O/W) emulsions were prepared by introducing hydrophobic tertiary amines (TAs) with varying alkane carbon numbers (ACNs) into the emulsion stabilized by sodium dodecyl benzene sulfonate (SDBS). TAs are converted to bicarbonate salts upon bubbling of CO2, which can form ion pairs with SDBS via electrostatic interaction, and then disrupt the stability of the emulsion. The reversible switch can be triggered by the removal of CO2. The ACN of TA, the concentration of SDBS/TA, the bubbling time of CO2, and the number of cycles are taken into account in order to study the controllable mechanism of these CO2-responsive emulsions. Because of the improved miscibility with oil, the ion pairs with TAs of larger ACNs can much more easily adhere to the oil phase, and then speed up the rupture rate of the oil droplets. The corresponding demulsification process is tracked by studying the interfacial tension, the zeta potential of the droplets, and microscope snapshots of all the systems. The UV-vis spectrophotometer analysis of the water phase and the 1H-nuclear magnetic resonance (1H NMR) test are further designed to comprehend the significance of ACNs and the solubility product of the formed ion pairs.

Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism.

The mammalian heart, the body's largest energy consumer, has evolved robust mechanisms to tightly couple fuel supply with energy demand across a wide range of physiologic and pathophysiologic states, yet, when compared with other organs, relatively little is known about the molecular machinery that directly governs metabolic plasticity in the heart. Although previous studies have defined Kruppel-like factor 15 (KLF15) as a transcriptional repressor of pathologic cardiac hypertrophy, a direct role for the KLF family in cardiac metabolism has not been previously established. We show in human heart samples that KLF15 is induced after birth and reduced in heart failure, a myocardial expression pattern that parallels reliance on lipid oxidation. Isolated working heart studies and unbiased transcriptomic profiling in Klf15-deficient hearts demonstrate that KLF15 is an essential regulator of lipid flux and metabolic homeostasis in the adult myocardium. An important mechanism by which KLF15 regulates its direct transcriptional targets is via interaction with p300 and recruitment of this critical co-activator to promoters. This study establishes KLF15 as a key regulator of myocardial lipid utilization and is the first to implicate the KLF transcription factor family in cardiac metabolism.

Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts.

Computer-aided lead optimization derives a unique, orally bioavailable inhibitor of the signal transducer and activator of transcription (Stat)3 Src homology 2 domain. BP-1-102 binds Stat3 with an affinity (K(D)) of 504 nM, blocks Stat3-phospho-tyrosine (pTyr) peptide interactions and Stat3 activation at 4-6.8 µM, and selectively inhibits growth, survival, migration, and invasion of Stat3-dependent tumor cells. BP-1-102-mediated inhibition of aberrantly active Stat3 in tumor cells suppresses the expression of c-Myc, Cyclin D1, Bcl-xL, Survivin, VEGF, and Krüppel-like factor 8, which is identified as a Stat3 target gene that promotes Stat3-mediated breast tumor cell migration and invasion. Treatment of breast cancer cells with BP-1-102 further blocks Stat3-NF-κB cross-talk, the release of granulocyte colony-stimulating factor, soluble intercellular adhesion molecule 1, macrophage migration-inhibitory factor/glycosylation-inhibiting factor, interleukin 1 receptor antagonist, and serine protease inhibitor protein 1, and the phosphorylation of focal adhesion kinase and paxillin, while enhancing E-cadherin expression. Intravenous or oral gavage delivery of BP-1-102 furnishes micromolar or microgram levels in tumor tissues and inhibits growth of human breast and lung tumor xenografts.

Research on the bearing creep characteristics and constitutive model of gangue filling body.

The creep characteristics and potential deformation patterns of gangue backfill material are crucial in backfill mining operations. This study utilizes crushed gangue from the Gangue Yard in Fuxin City as the research material. An in-house designed, large-scale, triaxial gangue compaction test system was used. Triaxial compaction creep tests were conducted on gangue materials with varying particle size distributions. Analysis was performed based on different particle sizes, stresses, and confinement pressures. The study investigates the creep characteristics of the gangue under different conditions and explores the underlying causes. It reveals the relationship between the creep deformation of gangue materials and the passage of time. Mathematical methods are applied to develop a triaxial compaction creep power law model for gangue backfill materials. Finally, the creep results are fitted using an empirical formula approach.

A novel role of Krüppel-like factor 8 in DNA repair in breast cancer cells.

Krüppel-like factor 8 (KLF8) regulates critical gene transcription and cellular events associated with cancer. However, the role of KLF8 in cancer remains largely unknown. Here, we report a surprisingly novel role for KLF8 in DNA repair in breast cancer cells. Comet, clonogenic, and WST-1 assays showed that KLF8 expression is required for protecting human breast cancer cells from doxorubicin-induced DNA damage and cell death. Western blotting indicated that overexpression of ectopic KLF8 attenuated the levels of the DNA damage marker γH2A.X in doxorubicin-treated PARP-1(+/+) but not PARP-1(-/-) mouse embryonic fibroblasts, whereas the PARP-1-binding-defective KLF8 mutant failed to do so. Interestingly, in response to the DNA damage, KLF8 was phosphorylated by the DNA-dependent protein kinase catalytic subunit and, subsequently, SUMOylated by SUMO E3 ligases protein inhibitors of activated STAT (PIASs), which depends upon the interaction of KLF8 with DNA-dependent protein kinase catalytic subunit, PIASs, and PARP-1 as well as their enzymatic activities. Lastly, we show evidence that KLF8 was recruited to the DNA damage site. These results suggest a novel role and mechanism for KLF8 in the regulation of DNA repair and therapeutic resistance in breast cancer cells.

Sensitization of pancreatic cancer cells to radiation by cerium oxide nanoparticle-induced ROS production.

Side effect of radiation therapy (RT) remains the most challenging issue for pancreatic cancer treatment. In this report we determined whether and how cerium oxide nanoparticles (CONPs) sensitize pancreatic cancer cells to RT. CONP pretreatment enhanced radiation-induced reactive oxygen species (ROS) production preferentially in acidic cell-free solutions as well as acidic human pancreatic cancer cells. In acidic environments, CONPs favor the scavenging of superoxide radical over the hydroxyl peroxide resulting in accumulation of the latter whereas in neutral pH CONPs scavenge both. CONP treatment prior to RT markedly potentiated the cancer cell apoptosis both in culture and in tumors and the inhibition of the pancreatic tumor growth without harming the normal tissues or host mice. Taken together, these results identify CONPs as a potentially novel RT-sensitizer as well as protectant for improving pancreatic cancer treatment. FROM THE CLINICAL EDITOR: Pancreatic tumors remain some of the most notoriously treatment-unresponsive malignancies. Cerium oxide nanoparticles may be capable of sensitizing such cells to radiotherapy, as demonstrated in this study.

Similar simulation of overburden movement characteristics under paste filling mining conditions.

The method of filling mining can solve the problem of surface subsidence caused by coal mining. Among them, it is crucial to study the mechanism of filler strength improvement timeliness and filler mining to control rock movement for filler mining. In this paper, by combining theoretical analysis and similar simulation experiments, compressive strength is used as the research parameter to conduct proportioning test research on paste filling similar materials such as coal gangue, fly ash, and cement. The results prove that the strengths of the test ratios can meet the strength design criteria and lay the foundation for the requirements of similar simulation experiments. In order to study the characteristics of overburden failure, stress and displacement in the process of filling mining, the key technical parameters of overburden movement are determined. Similar simulation experiments were conducted to study the movement and deformation of overburden rock and the displacement and stress distribution law of overburden rock in the coal mine under different filling rates and filling steps conditions. The results show that the filling rate and filling step are the keys to preventing the overlying rock from rupture and collapse, and the larger the filling rate is, the smaller the stress and displacement of the overburden; the larger the filling step is, the larger the displacement and stress change of the overburden, and vice versa. In addition, the displacement curve along the strike is basically an "arch" type distribution, and the stress variation trend is "large-small-large" with a "Z" type distribution. The research results are of great significance to guide the practice of filling mining and can provide the theoretical basis for its further promotion.

Detergent-insoluble PFN1 inoculation expedites disease onset and progression in PFN1 transgenic rats.

Accumulating evidence suggests a gain of elusive toxicity in pathogenically mutated PFN1. The prominence of PFN1 aggregates as a pivotal pathological hallmark in PFN1 transgenic rats underscores the crucial involvement of protein aggregation in the initiation and progression of neurodegeneration. Detergent-insoluble materials were extracted from the spinal cords of paralyzed rats afflicted with ALS and were intramuscularly administered to asymptomatic recipient rats expressing mutant PFN1, resulting in an accelerated development of PFN1 inclusions and ALS-like phenotypes. This effect diminished when the extracts derived from wildtype PFN1 transgenic rats were employed, as detergent-insoluble PFN1 was detected exclusively in mutant PFN1 transgenic rats. Consequently, the factor influencing the progression of ALS pathology in recipient rats is likely associated with the presence of detergent-insoluble PFN1 within the extracted materials. Noteworthy is the absence of disease course modification upon administering detergent-insoluble extracts to rats that already displayed PFN1 inclusions, suggesting a seeding rather than augmenting role of such extracts in initiating neuropathological changes. Remarkably, pathogenic PFN1 exhibited an enhanced affinity for the molecular chaperone DNAJB6, leading to the sequestration of DNAJB6 within protein inclusions, thereby depleting its availability for cellular functions. These findings shed light on a novel mechanism that underscores the prion-like characteristics of pathogenic PFN1 in driving neurodegeneration in the context of PFN1-related ALS.

Identification of poly (ADP-ribose) polymerase-1 (PARP-1) as a novel Kruppel-like factor 8-interacting and -regulating protein.

Krüppel-like factor 8 (KLF8) regulates critical gene transcription and cellular events associated with cancer. However, KLF8-interacting proteins remain largely unidentified. Using co-immunoprecipitation (co-IP), mass spectrometry, and GST pulldown assays, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a novel KLF8-interacting protein. Co-IP and Western blotting indicated that KLF8 is also a PARP-1 substrate. Mutation of the cysteines in the zinc finger domain of KLF8 abolished PARP-1 interaction. Surprisingly, immunofluorescent staining revealed a cytoplasmic mislocalization of KLF8 in PARP-1(-/-) cells or when the interaction was disrupted. This mislocalization was prevented by either PARP-1 re-expression or inhibition of CRM1-dependent nuclear export. Interestingly, co-IP indicated competition between PARP-1 and CRM1 for KLF8 binding. Cycloheximide chase assay showed a decrease in the half-life of KLF8 protein when PARP-1 expression was suppressed or KLF8-PARP-1 interaction was disrupted. Ubiquitination assays implicated KLF8 as a target of ubiquitination that was significantly higher in PARP-1(-/-) cells. Promoter reporter assays and chromatin immunoprecipitation assays showed that KLF8 activation on the cyclin D1 promoter was markedly reduced when PARP-1 was deleted or inhibited or when KLF8-PARP-1 interaction was disrupted. Overall, this work has identified PARP-1 as a novel KLF8-binding and -regulating protein and provided new insights into the mechanisms underlying the regulation of KLF8 nuclear localization, stability, and functions.

KLF8 promotes invasive outgrowth of breast cancer by inducing filopodium-like protrusions via CXCR4.

Post-therapeutic relapse remains the biggest challenge to breast cancer management. The re-initiation of proliferation of dormant tumor cells in either metastatic or primary tumor location marks the final rate-limiting step of malignancy and mortality. The underlying molecular mechanisms remain poorly understood. We have recently demonstrated that KLF8 promotes breast cancer metastasis via CXCR4 upregulation. Here we report a role and mechanisms for KLF8 in driving the recurrence-like tumor outgrowth in both secondary and primary sites in a CXCR4-dependent manner. Treatment of an MDA-MB-231 breast cancer cell variant with the CXCR4 ligand, CXCL12, induces formation of filopodia in monolayer culture and filopodium-like protrusions (FLPs) in 3D culture. The FLP+ cells proliferate significantly faster than FLP- cells in the 3D culture supplemented with CXCL12. Both the FLP formation and enhanced proliferation in the 3D culture can be prevented by silencing KLF8 expression in the cells. From this prevention, the cells can be rescued by overexpressing wild-type CXCR4 but not its inactive mutant form in the cells. Overexpression of KLF8 or CXCR4 in the cells dramatically enhances their invasive outgrowth and metastasis after being implanted into immunocompromised mice. Mechanistically, we found that the activated FAK was recruited to the nascent FLPs and that proliferation of the cells was completely prevented with a FAK-specific inhibitor. Taken together, these results shed new light on the role of KLF8 in promoting breast cancer recurrence, the fatal episode of the disease, by inducing CXCR4-dependent FLP formation.

ERK inactivation enhances stemness of NSCLC cells via promoting Slug-mediated epithelial-to-mesenchymal transition.

Rationale: The mitogen-activated protein kinase pathway (MAPK) is one of the major cancer-driving pathways found in non-small cell lung cancer (NSCLC) patients. ERK inhibitors (ERKi) have been shown to be effective in NSCLC patients with MAPK pathway mutations. However, like other MAPK inhibitors, ERKi rarely confers complete and durable responses. The mechanism of tumor relapse after ERKi treatment is yet defined. Methods: To best study the mechanism of tumor relapse after ERK inhibitor treatment in NSCLC patients, we treated various NSCLC cell lines and patient-derived xenograft (PDX) with ERK inhibitors and evaluated the enrichment of cancer stem cell (CSC) population. We then performed a Next-generation sequencing (NGS) to identify potential pathways that are responsible for the CSC enrichment. Further, the involvement of specific pathways was examined using molecular and cellular methods. Finally, we investigated the therapeutic benefits of ERKi treatment combined with JAK/STAT pathway inhibitor using cellular and xenograft NSCLC models. Results: We found that ERKi treatment expands the CSC population in NSCLC cells through enhanced epithelial-to-mesenchymal transition (EMT)-mediated cancer cell dedifferentiation. Mechanistically, ERK inactivation induces EMT via pSTAT3-mediated upregulation of Slug, in which, upregulation of miR-204 and downregulation of SPDEF, a transcription repressor of Slug, are involved. Finally, the JAK/STAT pathway inhibitor Ruxolitinib blocks the ERK inactivation-induced EMT and CSC expansion, as well as the tumor progression in xenograft models after ERKi treatment. Conclusions: This study revealed a potential tumor relapse mechanism of NSCLC after ERK inhibition through the unintended activation of the EMT program, ascertained the pSTAT-miR-204-SPDEF-Slug axis, and provided a promising combination inhibitor approach to prevent tumor relapse in patients.

Role of krüppel-like factor 8 for therapeutic drug-resistant multi-organ metastasis of breast cancer.

Metastasis and drug resistance are intertwined processes that are responsible for the vast majority of patient deaths from breast cancer. The underlying mechanisms remain incompletely understood. We previously demonstrated that KLF8 activates CXCR4 transcription in metastatic breast cancer. Here, we report a novel role of KLF8-CXCR4 signaling for converting single organ metastasis into multiple organ metastasis associated with chemotherapeutic resistance. We show that KLF8 expression in metastatic breast cancer cells can be over-induced by chemotherapeutic drugs. Analysis of data from large-cohorts of patients indicates that post-chemotherapy there is a close correlation between the aberrant high levels of KLF8 and CXCR4 and that this correlation is well associated with drug resistance, metastasis, and poor prognosis. To mimic their aberrant high levels, we overexpressed KLF8 or CXCR4 in a human breast cancer cell line known to metastasize only to the lungs after intravenous injection in nude mice. As expected, these cells become more resistant to chemotherapeutic drugs. Surprisingly, these KLF8 or CXCR4 overexpressing cells, even implanted orthotopically, metastasized extensively to multiple organs particularly the CXCL12-rich organs. Tube formation assay, Ki67 staining and Western blotting revealed that KLF8 or CXCR4 overexpression enhanced angiogenesis involving increased expression and secretion of VEGF protein. We also found that KLF8 or CXCR4 overexpression strongly enhanced formation of filopodium-like protrusions and proliferation via CXCR4 stimulation in a 3D culture model mimicking the colonization step of metastasis. Taken together, these results suggest that the chemo-induction of KLF8 upregulation be critical for drug resistance and systemic metastasis through enhanced tumor angiogenesis and colonization via CXCR4 over-activation and that KLF8-CXCR4 signaling axis may be a new therapeutic target for drug-resistant breast cancer metastasis.

Sensitization of breast cancer to Herceptin by redox active nanoparticles.

Herceptin-resistant tumor relapse remains a major clinical issue responsible for the poor prognosis of HER2+ breast cancer. Understanding the underlying mechanisms and finding a therapeutic solution are of paramount urgency to improve the patient management. Here we report that anticancer redox active cerium oxide nanoparticles (CONPs) can potently sensitize the cancer cells to the cytotoxicity of Herceptin. By comparing between Herceptin-sensitive and Herceptin-resistant human breast cancer cell lines under normoxic as well as hypoxic culture conditions, we found that in the presence of CONPs, Herceptin can kill the Herceptin-resistant cells equally effectively as it kills the Herceptin-sensitive cells under the hypoxic, but not normoxic, culture conditions by inhibiting the cell viability, survival and proliferation. Signaling analysis reveals that under the normoxic conditions, the levels of hypoxia induced factor 1α as well as vascular endothelial growth factor are higher in the Herceptin-resistant cells than that in the Herceptin-sensitive cells and are strongly induced once the culture is switched to the hypoxic conditions, which can be potently suppressed by CONPs. Treatment with CONPs plus Herceptin significantly slows down the primary tumor growth and lung metastasis of the Herceptin-resistant cells in a xenograft mouse model of orthotopic breast cancer through inhibiting the cell proliferation and survival as well as tumor angiogenesis. These results shed new lights on the mechanisms underlying the Herceptin resistance of the HER2+ breast cancer and provide insights into introducing CONPs-like agents to Herceptin-based therapy to improve treatment outcomes.

Signal transduction by focal adhesion kinase in cancer.

Cellular interactions with extracellular matrix play essential roles in tumor initiation, progression and metastasis. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase identified as a key mediator of signaling by integrins, a major family of cell surface receptors for extracellular matrix, as well as other receptors in both normal and cancer cells. FAK is activated by integrins through disruption of an auto-inhibitory intra-molecular interaction between its kinase domain and the amino terminal FERM domain. The activated FAK forms a binary complex with Src family kinases which can phosphorylate other substrates and trigger multiple intracellular signaling pathways to regulate various cellular functions. Subcellular localization of FAK in focal adhesions is essential for FAK signaling, which is another distinguishing feature of the kinase. Integrin-FAK signaling has been shown to activate a number of signaling pathways through phosphorylation and protein-protein interactions to promote tumorigenesis. FAK also plays a prominent role in tumor progression and metastasis through its regulation of both cancer cells and their microenvironments including cancer cell migration, invasion, epithelial to mesenchymal transition, and angiogenesis. More recently, a role for FAK in tumor initiation and progression has been demonstrated directly using xenograft as well as conditional knockout mouse models. In agreement with these experimental data, overexpression and activation of FAK have been found in a variety of human cancers. A number of small molecule inhibitors for FAK have been developed and in various phases of testing for cancer treatments. Overall, the intensive research on FAK signaling in cancer have yielded a wealth of information on this pivotal kinase and these and future studies are leading to potentially novel therapies for cancer.

Krüppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion.

Tumor invasion and metastasis are the main causes of death from cancer. Epithelial to mesenchymal transition (EMT) is a determining step for a cancer cell to progress from a noninvasive to invasive state. Krüppel-like factor 8 (KLF8) plays a key role in oncogenic transformation and is highly overexpressed in several types of invasive human cancer, including breast cancer. To understand the role of KLF8 in regulating the progression of human breast cancer, we first established stable expression of KLF8 in an immortalized normal human breast epithelial cell line. We found that KLF8 strongly induced EMT and enhanced motility and invasiveness in the cells, by analyzing changes in cell morphology and epithelial and mesenchymal marker proteins, and using cell migration and Matrigel invasion assays. Chromatin immunoprecipitations (ChIP), oligonucleotide precipitations, and promoter-reporter assays showed that KLF8 directly bound and repressed the promoter of E-cadherin independent of E boxes in the promoter and Snail expression. Aberrant elevation of KLF8 expression is highly correlated with the decrease in E-cadherin expression in the invasive human breast cancer. Blocking KLF8 expression by RNA interference restored E-cadherin expression in the cancer cells and strongly inhibited the cell invasiveness. This work identifies KLF8 as a novel EMT-regulating transcription factor that opens a new avenue in EMT research and suggests an important role for KLF8 in human breast cancer invasion and metastasis.

Regulation of Krüppel-like factor 8 by the NEDD4 E3 ubiquitin ligase.

Krüppel-like factor 8 (KLF8) plays many important roles in various diseases, especially cancer. Previous studies have shown that KLF8 is regulated by ubiquitylation. The molecular mechanism underlying this posttranslational modification of KLF8, however, has not been investigated. Reported here is our identification of the neural precursor cell expressed, developmentally down-regulated 4 (NEDD4) as the E3 ubiquitin ligase for this modification. By co-immunoprecipitation and ubiquitylation assays, we determined that KLF8 interacts with NEDD4 and is ubiquitylated by NEDD4. By site-directed mutagenesis and pharmacological inhibition of MEK, we found that the ubiquitylation of KLF8 by NEDD4 depends upon the phosphorylation of KLF8 at serine 48 by ERK. Cycloheximide chase analysis, target gene promoter reporter assay and fluorescent staining indicated that NEDD4 plays a critical role in promoting the stability and transcriptional activity of KLF8 in the nucleus. Taken together, this work identified NEDD4 as a novel E3 ubiquitin ligase for KLF8 that provides insights into targeting the KLF8-NEDD4 axis to treat various types of cancer associated with overexpression of both proteins.

Cerium Oxide Nanoparticles Sensitize Pancreatic Cancer to Radiation Therapy through Oxidative Activation of the JNK Apoptotic Pathway.

Side effects of radiation therapy (RT) remain the most challenging issue for pancreatic cancer treatment. Cerium oxide nanoparticles (CONPs) are currently being tested in pre-clinical trials as an adjuvant to sensitize pancreatic cancer cells to RT and protect normal tissues from the harmful side effects. CONPs were not able to significantly affect RT-induced DNA damage in cancer cells, thereby ruling out sensitization through increased mitotic catastrophe. However, activation of c-Jun terminal kinase (JNK), a key driver of RT-induced apoptosis, was significantly enhanced by co-treatment with CONPs and RT in pancreatic cancer cells in vitro and human pancreatic tumors in nude mice in vivo compared to CONPs or RT treatment alone. Further, CONP-driven increase in RT-induced JNK activity was associated with a marked increase in Caspase 3/7 activation, indicative of apoptosis. We have previously shown that CONPs increase reactive oxygen species (ROS) production in cancer cells. ROS has been shown to drive the oxidation of thioredoxin 1 (TRX1) which results in the activation of apoptosis signaling kinase 1 (ASK1). The increase in ASK1 activation following the co-treatment with CONPs followed by RT suggests that the increased JNK activation is the result of increased TRX1 oxidation. The ability of CONPs to sensitize pancreatic cancer cells to RT was mitigated when the TRX1 oxidation was prevented by mutagenesis of a cysteine residue or when the JNK activation was blocked by an inhibitor. Taken together, these data demonstrate an important mechanism for CONPs in specifically killing cancer cells and provide novel insights into the utilization of CONPs as a radiosensitizer and therapeutic agent for pancreatic cancer.

Regulation of focal adhesion kinase by a novel protein inhibitor FIP200.

Focal adhesion kinase (FAK) is a major mediator of integrin signaling pathways. The mechanisms of regulation of FAK activity and its associated cellular functions are not very well understood. Here, we present data suggesting that a novel protein FIP200 functions as an inhibitor for FAK. We show the association of endogenous FIP200 with FAK, which is decreased upon integrin-mediated cell adhesion concomitant with FAK activation. In vitro- and in vivo-binding studies indicate that FIP200 interacts with FAK through multiple domains directly. FIP200 bound to the kinase domain of FAK inhibited its kinase activity in vitro and its autophosphorylation in vivo. Overexpression of FIP200 or its segments inhibited cell spreading, cell migration, and cell cycle progression, which correlated with their inhibition of FAK activity in vivo. The inhibition of these cellular functions by FIP200 could be rescued by coexpression of FAK. Last, we show that disruption of the functional interaction between endogenous FIP200 with FAK leads to increased FAK phosphorylation and partial restoration of cell cycle progression in cells plated on poly-L-lysine, providing further support for FIP200 as a negative regulator of FAK. Together, these results identify FIP200 as a novel protein inhibitor for FAK.

Cancer stem cells and chemoresistance: The smartest survives the raid.

Chemoresistant metastatic relapse of minimal residual disease plays a significant role for poor prognosis of cancer. Growing evidence supports a critical role of cancer stem cell (CSC) behind the mechanisms for this deadly disease. This review briefly introduces the basics of the conventional chemotherapies, updates the CSC theories, highlights the molecular and cellular mechanisms by which CSC smartly designs and utilizes multiple lines of self-defense to avoid being killed by chemotherapy, and concisely summarizes recent progress in studies on CSC-targeted therapies in the end, with the hope to help guide future research toward developing more effective therapeutic strategies to eradicate tumor cells in the patients.