Canagliflozin inhibits growth of hepatocellular carcinoma via blocking glucose-influx-induced ß-catenin activation.

Accelerated glucose metabolism is critical in hepatocarcinogenesis, but the utilities of different glucose transporter inhibitors in treating hepatocellular carcinoma (HCC) remain largely uncharacterized. In this study, we examined a collection of glucose transporter inhibitors and found differential anti-HCC effects among these compounds. Canagliflozin (CANA), phloretin, and WZB117 decreased cellular glucose influx, but only CANA showed potent growth inhibition in HCC, which indicated a glucose-independent anti-HCC mechanism. Notably, we found that CANA treatment significantly downregulated the expression of ß-catenin in HCC cells in. By co-treating cells with cycloheximide and MG-132, we proved that CANA promoted proteasomal degradation of ß-catenin protein by increasing phosphorylation of ß-catenin, and CANA-induced inactivation of protein phosphatase 2A was identified being responsible for this effect. Moreover, using Huh7 xenografted tumor model, CANA treatment was shown to delay tumor growth and improved the survival of HCC bearing mice. Our study highlights the unique dual ß-catenin-inhibition mechanisms of CANA, which may provide new thoughts on treating HCC patient with concurrent diabetes, and, furthermore, on developing novel treatment targeting metabolic reprogram and/or WNT/ß-catenin signaling in HCC.

Nurses' intention to resign and avoidance of emergency department violence: A moderated mediation model.

BACKGROUND: Studies that examined the negative impact of violence in emergency departments on nurses' leave and avoidance behavior are well-documented. However, few studies provided an integrated model of how and when violence influences their leave and avoidance behavior. PURPOSE: The study adopted Affective Events Theory to propose and examine a model of violent events, negative emotions, and (leave and avoidance) behaviors on nurses in emergency departments and further analyzed whether the model is salient to nurses' occupational burnout, nursing experience, and nursing rank. METHOD: The sample included 123 emergency department nurses at a teaching hospital in northern, Taiwan. RESULTS: All participants had experienced violent incidents within the preceding 6 months. Moderated mediation analysis suggested that nurses experienced one of two emotional processes following violent incidents: "violence-negative feelings toward work-intention to resign" or "violence-negative emotion and physical symptoms-avoidance tendencies." Moreover, nurses with high burnout levels expressed weaker intention to resign after violent incidents, while nurses with more experience and higher rank were less likely to avoid violence after violent incidents. CONCLUSION: Emergency nurses do not simply elect to escape but may engage in avoidance behavior. This study revealed that how violent incidents affect nurses' resignation or avoidance behaviors depends on how they feel. Occupational burnout and nurses' attributes affected their behavior.

Inhibition of protein phosphatase 5 suppresses non-small cell lung cancer through AMP-activated kinase activation.

OBJECTIVES: Non-small cell lung cancer (NSCLC) continues to be the top cause of cancer death. To improve the treatment of lung cancer, there is necessity to identify novel oncogenes and investigate their effects on lung carcinogenesis. Protein phosphatase 5 (PP5) has long been known to regulate stress-induced apoptosis and cell proliferation. Recently, PP5 has been found overexpressed and emerged as a viable therapeutic target in various human cancers, but its role in NSCLC remains elusive. MATERIALS AND METHODS: The expression of PP5 in NSCLC cell lines (A549, H358, and H460) and human tumor samples were examined. Protein phosphatase inhibitors, cantharidin and norcantharidin, were used as proof-of-concept compounds to investigate the pathological function of PP5 in NSCLC. Apoptosis and cellular signaling were analyzed. In vivo efficacy was determined in nude mice with H460 xenograft. RESULTS AND CONCLUSION: We found that PP5 was more highly expressed in human lung tumor samples than in adjacent normal tissues. Overexpression of PP5 promoted cell proliferation, colony formation, and sphere-forming ability of A549 cells. Inhibition of PP5 phosphatase activity by cantharidin induced significant apoptosis and upregulated AMP-activated protein kinase (AMPK) signaling. Importantly, we found that PP5-mediated dephosphorylation of AMPK determines the in vitro anti-NSCLC effects of cantharidin. Consistent with our in vitro data, PP5 inhibition suppressed H460 tumor growth and upregulated p-AMPK in tumor samples. Our results demonstrate that PP5 inhibition suppresses tumor growth via activating AMPK signaling. Targeting oncogenic PP5 represents an attractive therapeutic strategy for treating lung cancer.

Protein phosphatase 5 promotes hepatocarcinogenesis through interaction with AMP-activated protein kinase.

The serine-threonine protein phosphatase family members are known as critical regulators of various cellular functions, such as survival and transformation. Growing evidence suggests that pharmacological manipulation of phosphatase activity exhibits therapeutic benefits. Ser/Thr protein phosphatase 5 (PP5) is known to participate in glucocorticoid receptor (GR) and stress-induced signaling cascades that regulate cell growth and apoptosis, and has been shown to be overexpressed in various human malignant diseases. However, the role of PP5 in hepatocellular carcinoma (HCC) and whether PP5 may be a viable therapeutic target for HCC treatment are unknown. Here, by analyzing HCC clinical samples obtained from 215 patients, we found that overexpression of PP5 is tumor specific and associated with worse clinical outcomes. We further characterized the oncogenic properties of PP5 in HCC cells. Importantly, both silencing of PP5 with lentiviral-mediated short hairpin RNA (shRNA) and chemical inhibition of PP5 phosphatase activity using the natural compound cantharidin/norcantharidin markedly suppressed the growth of HCC cells and tumors in vitro and in vivo. Moreover, we identified AMP-activated protein kinase (AMPK) as a novel downstream target of oncogenic PP5 and demonstrated that the antitumor mechanisms underlying PP5 inhibition involve activation of AMPK signaling. Overall, our results establish a pathological function of PP5 in hepatocarcinogenesis via affecting AMPK signaling and suggest that PP5 inhibition is an attractive therapeutic approach for HCC.

Palbociclib induces activation of AMPK and inhibits hepatocellular carcinoma in a CDK4/6-independent manner.

Palbociclib, a CDK4/6 inhibitor, has recently been approved for hormone receptor-positive breast cancer patients. The effects of palbociclib as a treatment for other malignancies, including hepatocellular carcinoma (HCC), are of great clinical interest and are under active investigation. Here, we report the effects and a novel mechanism of action of palbociclib in HCC. We found that palbociclib induced both autophagy and apoptosis in HCC cells through a mechanism involving 5' AMP-activated protein kinase (AMPK) activation and protein phosphatase 5 (PP5) inhibition. Blockade of AMPK signals or ectopic expression of PP5 counteracted the effect of palbociclib, confirming the involvement of the PP5/AMPK axis in palbociclib-mediated HCC cell death. However, CDK4/6 inhibition by lentivirus-mediated shRNA expression did not reproduce the effect of palbociclib-treated cells, suggesting that the anti-HCC effect of palbociclib is independent of CDK4/6. Moreover, two other CDK4/6 inhibitors (ribociclib and abemaciclib) had minimal effects on HCC cell viability and the PP5/AMPK axis. Palbociclib also demonstrated significant tumor-suppressive activity in a HCC xenograft model, which was associated with upregulation of pAMPK and PP5 inhibition. Finally, we analyzed 153 HCC clinical samples and found that PP5 expression was highly tumor specific and was associated with poor clinical features. Taken together, we conclude that palbociclib exerted antitumor activity against HCC through the PP5/AMPK axis independent of CDK4/6. Our findings provide a novel mechanistic basis for palbociclib and reveal the therapeutic potential of targeting PP5/AMPK signaling with a PP5 inhibitor for the treatment of hepatocellular carcinoma.

Dovitinib Acts As a Novel Radiosensitizer in Hepatocellular Carcinoma by Targeting SHP-1/STAT3 Signaling.

PURPOSE: Hepatocellular carcinoma (HCC) is among the most lethal human malignancies, and curative therapy is not an option for most patients. There is growing interest in the potential benefit of combining targeted therapies with radiation therapy (RT). This study aimed to characterize the efficacy and mechanism of an investigational drug, dovitinib, used in combination with RT. METHODS AND MATERIALS: HCC cell lines (PLC5, Hep3B, SK-Hep1, HA59T, and Huh-7) were treated with dovitinib, RT, or both, and apoptosis and signal transduction were analyzed. RESULTS: Dovitinib treatment resulted in Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1)-mediated downregulation of p-STAT3 and promoted potent apoptosis of HCC cells. Ectopic expression of STAT3, or inhibition of SHP-1, diminished the effects of dovitinib on HCC cells. By ectopic expression and purified recombinant proteins of various mutant forms of SHP-1, the N-SH2 domain of SHP-1 was found to be required for dovitinib treatment. Overexpression of STAT3 or catalytic-dead mutant SHP-1 restored RT-induced reduction of HCC cell survival. Conversely, ectopic expression of SHP-1 or activation of SHP-1 by dovitinib enhanced the effects of RT against HCC in vitro and in vivo. CONCLUSIONS: SHP-1/STAT3 signaling is critically associated with the radiosensitivity of HCC cells. Combination therapy with RT and the SHP-1 agonist, such as dovitinib, resulted in enhanced in vitro and in vivo anti-HCC effects.

Nurse occupational burnout and patient-rated quality of care: The boundary conditions of emotional intelligence and demographic profiles.

AIM: Most previous studies on the relationship between occupational burnout and the quality of care among nurses have used self-reported data on the quality of care from nurses, thus rendering evaluating the relationship between burnout and the quality of care difficult. Hospitals increasingly hire contract nurses and high turnover rates remain a concern. Little is known about whether nurses' emotional intelligence and demographic factors such as contract status, tenure, and marital status affect the quality of care when burnout occurs. This study investigated the relationship between burnout and patient-rated quality of care and investigated the moderating role of emotional intelligence and demographic variables. METHODS: Hierarchical moderated regression was used to analyze 98 sets of paired data obtained from nurses and their patients at a teaching hospital in northern Taiwan. RESULTS: The results suggest that occupational burnout has a less unfavorable effect on the quality of care from permanent, married, and senior nurses. CONCLUSION: Nursing management should pay particular attention to retaining permanent, married, and senior nurses. To ensure a sustainable nursing workforce in the future, newly graduated registered nurses should have access to permanent positions and opportunities for long-term professional development. In addition, married nurses should be provided with flexible work-family arrangements to ensure their satisfaction in the nursing profession.