: Cancer cells reprogram cellular metabolism to fulfill their needs for rapid growth and metastasis. However, the mechanism controlling this reprogramming is poorly understood. We searched for ...upregulated signaling in metastatic colorectal cancer and investigated the mechanism by which Glut3 promotes tumor metastasis.
: We compared RNA levels and glycolytic capacity in primary and metastatic colon cancer. The expression and association of Glut3 with clinical prognosis in colon cancer tissues was determined by immunohistochemistry. Glut3 gain-of-function and loss-of-function were established using colon cancer HCT116, HT29, and metastatic 116-LM cells, and tumor invasiveness and stemness properties were evaluated. Metabolomic profiles were analyzed by GC/MS and CE-TOF/MS. The metastatic burden in mice fed a high-fat sucrose diet was assessed by intravenous inoculation with Glut3 knockdown 116-LM cells.
: Upregulation of glycolytic genes and glycolytic capacity was detected in metastatic colorectal cancer cells. Specifically, Glut3 overexpression was associated with metastasis and poor survival in colorectal cancer patients. Mechanistically, Glut3 promoted invasiveness and stemness in a Yes-associated protein (YAP)-dependent manner. Activation of YAP in turn transactivated Glut3 and regulated a group of glycolytic genes. Interestingly, the expression and phosphorylation of PKM2 were concomitantly upregulated in metastatic colorectal cancer, and it was found to interact with YAP and enhance the expression of Glut3. Importantly, a high-fat high-sucrose diet promoted tumor metastasis, whereas the inhibition of either Glut3 or YAP effectively reduced the metastatic burden.
: Activation of the Glut3-YAP signaling pathway acts as a master activator to reprogram cancer metabolism and thereby promotes metastasis. Our findings reveal the importance of metabolic reprogramming in supporting cancer metastasis as well as possible therapeutic targets.
Dysregulation of hormones is considered a risk factor for obesity‐mediated breast tumorigenesis; however, obesity is associated with poor outcomes among women diagnosed with triple‐negative breast ...cancer (TNBC), which is a hormone‐independent breast cancer subtype. Thus, identifying the driving force behind the obesity‐breast cancer relationship is an urgent need. Here it is identified that diet‐induced obesity (DIO) facilitates tumorigenesis of TNBC cells. Mechanistically, DIO induces a metabolic addiction to fatty acid oxidation (FAO), accompanied by coordinated activation of Yes‐associated protein (YAP) signaling. Specifically, YAP governs mitochondrial redox homeostasis via transcriptional regulation of antioxidant‐related enzymes, which renders tumor cells capable of extenuating FAO‐elicited mitochondrial oxidative stress. Moreover, adipocytes‐derived fatty acids are identified to be responsible for enhancing the FAO‐YAP axis and antioxidative capacity, and higher expression of an obesity signature in breast cancer patients is positively correlated with YAP signaling and antioxidant genes. The findings uncover the crucial role of YAP in dictating mitochondrial redox homeostasis for obesity‐mediated metabolic adaptation and breast tumor progression.
It is identified that Yes‐associated protein (YAP) governs mitochondria redox homeostasis through the regulation of antioxidant gene expressions in obesity‐associated breast cancer cells. Activation of YAP alleviates metabolic stress from fatty acid oxidation, resulting in decreased metabolic stress and the promotion of a survival advantage.
A factor that combines tunnel depth and incident wavelength has been numerically determined to dominate the seismic responses of a tunnel in rocks that are subjected to harmonic
P
- and
S
-waves. ...This study applies the dynamic finite element method to investigate the seismic response of shallow overburden tunnels. Seismically induced stress increments in the lining of a circular tunnel that is subjected to an incident harmonic
R
-wave are examined. The determination of
R
-wave considers the dominant frequency of acceleration history of the 1999 Chi–Chi earthquake measured near the site with damage to two case tunnels at specifically shallow depth. An analysis reveals that the normalized seismically induced axial, shear and flexural stress increments in the lining of a tunnel reach their respective peaks at the depth
h
/
λ
= 0.15, where the ground motion that is generated by an incident of
R
-wave has its maximum. The tunnel radius has a stronger effect on seismically induced stress increments than does tunnel depth. A greater tunnel radius yields higher normalized seismically induced axial stress increments and lower normalized seismically induced shear and flexural stress increments. The inertia of the thin overburden layer above the tunnel impedes the propagation of the wave and affects the motion of the ground around the tunnel. With an extremely shallow overburden, such an effect can change the envelope of the normalized seismically induced stress increments from one with a symmetric four-petal pattern into one with a non-symmetric three-petal pattern. The simulated results may partially elucidate the spatial distributions of cracks that were observed in the lining of the case tunnels.
Treatment of triple-negative breast cancer (TNBC) remains an unmet clinical need owing to its lack of an efficient therapeutic target. The targeting of DNA repair by poly(ADP-ribose) polymerase ...(PARP) inhibitors has shown benefit for patients with the BRCA variation. However, sensitivities to the PARP inhibitors were reported regardless of BRCA status. Thus, exploring the underlying mechanisms is imperative. Herein, we identified that breast cancer cells with an elevated expression of protein arginine methyl transferase 1 (PRMT1) was associated with therapeutic sensitivity to the PARP inhibitor olaparib. The results of cell viability and colony formation assays indicated that the suppression of PRMT1 by small hairpin RNA or by the chemical inhibitor increased sensitivity to olaparib in human TNBC MDA-MB-231 and BT549 cells. Bioinformatic analysis revealed that PRMT1 expression was significantly associated with the MYC signature, and TNBC cells with higher PRMT1 and the MYC signature were associated with therapeutic sensitivity to olaparib. Mechanistic studies further demonstrated that knockdown of PRMT1 reduced the c-Myc protein level and downregulated the expression of MYC downstream targets, whereas overexpression of PRMT1 enhanced c-Myc protein expression. Moreover, the overexpression of PRMT1 promoted c-Myc protein stability, and the inhibition of PRMT1 downregulated c-Myc protein stability. Accordingly, the knockdown of PRMT1 inhibited homologous recombination gene expression. These data indicate that PRMT1 is instrumental in regulating DNA repair, at least in part, by modulating c-Myc signaling. Our data highlighted the PRMT1/c-Myc network as a potential therapeutic target in patients with TNBC.
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer as it shows a high capacity for metastasis and poor prognoses. Metabolic reprogramming is one of the hallmarks of ...cancer, and aberrant glycolysis was reported to be upregulated in TNBC. Thus, identifying metabolic biomarkers for diagnoses and investigating cross-talk between glycolysis and invasiveness could potentially enable the development of therapeutics for patients with TNBC. In order to determine novel and reliable metabolic biomarkers for predicting clinical outcomes of TNBC, we analyzed transcriptome levels of glycolysis-related genes in various subtypes of breast cancer from public databases and identified a distinct glycolysis gene signature, which included ENO1, SLC2A6, LDHA, PFKP, PGAM1, and GPI, that was elevated and associated with poorer prognoses of TNBC patients. Notably, we found a transcription factor named Y-box-binding protein 1 (YBX1) to be strongly associated with this glycolysis gene signature, and it was overexpressed in TNBC. A mechanistic study further validated that YBX1 was upregulated in TNBC cell lines, and knockdown of YBX1 suppressed expression of those glycolytic genes. Moreover, YBX1 expression was positively associated with epithelial-to-mesenchymal transition (EMT) genes in breast cancer patients, and suppression of YBX1 downregulated expressions of EMT-related genes and tumor migration and invasion in MDA-MB-231 and BT549 TNBC cells. Our data revealed an YBX1-glycolysis-EMT network as an attractive diagnostic marker and metabolic target in TNBC patients.
Aurora kinases (AURKs) are mitotic kinases important for regulating cell cycle progression. Small-molecule inhibitors of AURK have shown promising antitumor effects in multiple cancers; however, the ...utility of these inhibitors as inducers of cancer cell death has thus far been limited. Here, we examined the role of the Bcl-2 family proteins in AURK inhibition–induced apoptosis in colon cancer cells. We found that alisertib and danusertib, two small-molecule inhibitors of AURK, are inefficient inducers of apoptosis in HCT116 and DLD-1 colon cancer cells, the survival of which requires at least one of the two antiapoptotic Bcl-2 family proteins, Bcl-xL and Mcl-1. We further identified Bcl-xL as a major suppressor of alisertib- or danusertib-induced apoptosis in HCT116 cells. We demonstrate that combination of a Bcl-2 homology (BH)3-mimetic inhibitor (ABT-737), a selective inhibitor of Bcl-xL, Bcl-2, and Bcl-w, with alisertib or danusertib potently induces apoptosis through the Bcl-2 family effector protein Bax. In addition, we identified Bid, Puma, and Noxa, three BH3-only proteins of the Bcl-2 family, as mediators of alisertib–ABT-737-induced apoptosis. We show while Noxa promotes apoptosis by constitutively sequestering Mcl-1, Puma becomes associated with Mcl-1 upon alisertib treatment. On the other hand, we found that alisertib treatment causes activation of caspase-2, which promotes apoptosis by cleaving Bid into truncated Bid, a suppressor of both Bcl-xL and Mcl-1. Together, these results define the Bcl-2 protein network critically involved in AURK inhibitor–induced apoptosis and suggest that BH3-mimetics targeting Bcl-xL may help overcome resistance to AURK inhibitors in cancer cells.
The combination of tunnel depth and incident wavelength has been numerically revealed as a key factor dominating seismic responses of a tunnel in a homogenous rock layer. To investigate further the ...seismic response of a tunnel in double-layer rocks and to clarify the effect caused by the layered rocks, this study applies the dynamic finite element method and investigates seismically induced stress increments in the lining of a circular tunnel subjected to an incident harmonic P- and S-wave. Analysis results reveal that the normalized seismically induced stress increments are maximal when normalized tunnel depth is 0.25 multiplying an odd number. Additionally, normalized seismically induced stress increments are minimal when normalized tunnel depth is 0.25 multiplying an even number. Further, the impedance ratio links the seismic responses of upper and lower rock layers subjected to incident harmonic waves, which may significantly amplify incident stress in the upper rock layer, thereby affecting the seismically induced stress increments in a tunnel lining.
•Seismic responses of tunnels at various depths in double-layer rocks are studied numerically.•Seismic induced stresses are maximal when normalized tunnel depth is 0.25 multiplying an odd.•Wave reflection from free surface and layer boundary and tunnel scattering amplify stress.•Impedance ratio links seismic responses of double rock layers subjected to an incident wave.•Impedance ratio affects the seismically induced stress increments in a tunnel lining.
► We model the responses of tunnels at various depths when they are subjected to seismic excitation. ► Seismically induced stress in lining is strongly correlated with depth and incident wavelength. ...► Stress amplification is particularly pronounced at a depth of 0.25 times wavelength. ► Stress amplification is caused by reflection of wave from free surface and tunnel scattering effect. ► Shallow tunnels in weak rock and deep tunnels in competent rocks are particularly vulnerable.
This study investigates the influence of the depth of a tunnel on its seismic damage. Dynamical finite element analysis based on a numerical model of rock mass and tunnel lining is carried out and the incident waves are modeled as harmonic S- and P-waves. The analysis reveals that seismically induced stress is strongly correlated with the depth and the wavelength of the incident wave: when the depth is one quarter of the wavelength, the amplification of the seismically induced stress is particularly pronounced. The amplification is caused by the reflection of waves from the free surface and the scattering effect of the tunnel. A case history of a seismically damaged tunnel is considered to confirm this amplification phenomenon. Damage potential to a tunnel is greatest when the tunnel is at a depth that is close to 0.25 times to the wavelength, so shallow tunnels in weak rock and deep tunnels in competent rocks are particularly vulnerable.
•Hydrogeological approaches is applied to characterize a site of a shaft for a highway tunnel.•More than 3400 fracture data acquired to establish a model that characterizes fractured rock ...mass.•Permeability tensor of rock and potential flowing paths of groundwater to the shaft is determined.•Two plans for mitigating water inrush during shaft construction are proposed accordingly.
The inrush of water during excavation is one of the most difficult challenges in modern underground engineering. Studies of the permeability of a rock mass, and especially potential paths for the flow of groundwater, are important for mitigation. This study considers a ventilation shaft for a twin-bore four-lane highway tunnel, and applies hydrogeological approaches to characterize the site, and to propose corresponding plans for mitigating water inrush. Based on detailed descriptions on outcrops, a scanline survey, and the interpretation of scanned images of four boreholes with a total length of 480m that were obtained using a televiewer, more than 3400 data concerning the attitudes and locations of fractures are acquired to classify the strata close to the study site as terrace alluvium, regolith and fractured rock masses. Five predominant fracture sets, with corresponding parameters of their respective spatial distributions that are determined by stereographic projection analysis and statistical analysis, are characterized to establish a model to characterize the fractures of fractured rock masses. Taking into account the locations where high equivalent hydraulic conductivity are identified, this study presumes a model that provides potential paths of groundwater that flows to the shaft, including specific locations, scopes and directions of groundwater flows. Another model that is inferred based on the conventional Qlogging method is also provided for comparison. Two plans for mitigating water inrush during shaft construction are proposed based on the models of the spatial distribution of fractures and potential paths of flowing groundwater to the shaft. The adopted plan involves grouting in the regolith stratum to form a water-proof curtain that is applied in the ground surface or inside the shaft, radial grouting in the fractured rock masses that is applied inside the shaft, and the installation of pumping wells at the ground surface to draw down the groundwater table.
“Leading” display is one of the conventional Internet homepage design methods for presenting dynamic information on visual display terminals (VDTs). This study investigated the effects of display ...screen type (cathode ray tube and liquid crystal display), Chinese typography (computer type, standard Kai type), text/background color combinations (white-on-black, black-on-white, blue-on-white, red-on-white, blue-on-yellow, and green-on-white), speed (250 and 300
wpm), and jump length (0.35, 0.7, and 1.05
cm) for leading display on subjects’ reading performance. The results of this study showed that screen type, Chinese typography, and speed had no significant effect on subjects’ reading performance. Text/background color combination and jump length, however, were significant factors for subjects’ reading performance. Additionally, the interaction between jump length and color combination of leading display also had a significant effect on subjects’ reading performance. When the jump length of leading display was at lower levels (that is, 0.35 and 0.7
cm), users’ reading performance was not significantly different under different levels of text/background color combination. However, when the jump length was at a higher level (1.05
cm), subjects’ reading performance for the text/background color combinations with higher color difference was significantly better than performance for the color combinations with lower color difference.
Screen type, Chinese typography, text/background color combination, speed, and jump length are key factors for Chinese leading display that affect users’ reading performance. The results from this study may assist in designing Chinese leading display and in improving the performance of leading display information users.
PDF
