BET inhibition induces synthetic lethality in PTEN deficient colorectal cancers via dual action on p21CIP1/WAF1.

Loss of PTEN tumor suppressor is an important event during colorectal cancer (CRC) development and is a target for therapeutic exploitation. This study reports that bromodomain and extra-terminal motif (BET) is a synthetic lethal partner of PTEN in CRC. BET inhibition (BETi) selectively induced G1 cell cycle arrest and apoptosis in PTEN-/- CRC. Further, BETi selectively and dose-dependently suppressed the growth of PTEN-/- CRC tumor xenografts in mice and patient-derived organoids. Mechanistically, PTEN-deficient CRC cells elevated the level of cytoplasmic p21CIP1/WAF1 that is hyper-phosphorylated at Thr145 by AKT. BETi suppressed AKT activation in PTEN-deficient CRC cells, followed by the reduction in p21 phosphorylation at Thr145, thereby promoting its nuclear translocation. In addition, BETi suppressed MYC level and this in turn increased the total p21 level in the nuclei. Over-expression of a phospho-mimetic p21 mutant (T145D) significantly rescued the BETi effect on PTEN-deficient CRC. These results suggest that BETi has a dual action on p21: elevating the level of p21 by inhibiting MYC and converting the oncogenic (cytoplasmic) p21 into the tumor-suppressive (nuclear) p21 by inhibiting AKT. Taken together, this study identified the synthetic lethal interaction between PTEN and BET, and provides a potential actionable target for CRC with PTEN loss.

Coupled air lasing gain and Mie scattering loss: an aerosol effect in filament-induced plasma spectroscopy.

Femtosecond laser filament-induced plasma spectroscopy (FIPS) demonstrates great potential in remote sensing for identifying atmospheric pollutant molecules. Due to the widespread aerosols in the atmosphere, remote detection based on FIPS would be affected by both the excitation and the propagation of fingerprint fluorescence, which still remain elusive. Here the physical model of filament-induced aerosol fluorescence is established to reveal the combined effect of Mie scattering and amplification spontaneous emission, which is subsequently proven by experimental results, the dependence of the backward fluorescence on the interaction length between filaments and aerosols. These findings provide an insight into the complicated aerosol effect in the overall physical process of FIPS including propagation, excitation, and emission, paving the way to its practical application in atmospheric remote sensing.

ER translocon inhibitor ipomoeassin F inhibits triple-negative breast cancer growth via blocking ER molecular chaperones.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer where no effective therapy has been developed. Here, we report that the natural product ER translocon inhibitor ipomoeassin F is a selective inhibitor of TNBC cell growth. A proteomic analysis of TNBC cells revealed that ipomoeassin F significantly reduced the levels of ER molecular chaperones, including PDIA6 and PDIA4, and induced ER stress, unfolded protein response (UPR) and autophagy in TNBC cells. Mechanistically, ipomoeassin F, as an inhibitor of Sec61α-containing ER translocon, blocks ER translocation of PDIA6, inducing its proteasomal degradation. Silencing of PDIA6 or PDIA4 by RNA interferences or treatment with a small molecule inhibitor of the protein disulfide isomerases in TNBC cells successfully recapitulated the ipomoeassin F phenotypes, including the induction of ER stress, UPR and autophagy, suggesting that the reduction of PDIAs is the key mediator of the pharmacological effects of ipomoeassin F. Moreover, ipomoeassin F significantly suppressed TNBC growth in a mouse tumor xenograft model, with a marked reduction in PDIA6 and PDIA4 levels in the tumor samples. Our study demonstrates that Sec61α-containing ER translocon and PDIAs are potential drug targets for TNBC and suggests that ipomoeassin F could serve as a lead for developing ER translocon-targeted therapy for TNBC.

Sub-ppb NaCl aerosol detection at a distance of 30 meters by femtosecond laser induced plasma spectroscopy.

In this work, sub-ppb aerosol detection is achieved by femtosecond laser filament with a single pulse energy of 4 mJ at a distance of 30 m. A concave mirror with an open aperture of 41.4 cm is employed in an off-axis optical system to focus the femtosecond laser beam and collect the fluorescence of NaCl aerosol. The simulation and experimental results show that the astigmatism can be greatly reduced when femtosecond laser beam is incident non-symmetrically on the concave mirror. Compared with the case that femtosecond laser strikes at the center of the concave mirror, the intensity of acoustic signal emitted from the optical filament is increased by 69.5 times, and the detection of limit of sodium element in aerosol is reduced by 86%, which is down to 0.32 ppb. The improved excitation scheme in this work utilizes the nonsymmetrical beam spot on the concave mirror to compensate the non-symmetry induced by the off-axis setup, reducing the astigmatism of the focusing laser beam and decreasing the sodium chloride aerosol's detection of limit.

MDM2 inhibition is synthetic lethal with PTEN loss in colorectal cancer cells via the p53-dependent mechanism.

Colorectal cancer (CRC) driven by PTEN deficiency exhibits high risk of metastasis, advancement of tumor stages and chemotherapy resistance, where no effective therapy has been developed. In this study, we performed a synthetic lethal drug screening in CRC and found that PTEN-deficient CRC cells are highly vulnerable to MDM2 inhibition. MDM2 inhibitor treatment or its silencing selectively inhibited the growth of PTEN-deficient CRC in vitro and in mice models. Mechanistically, PTEN loss increased the level of active AKT and subsequently increased MDM2 phosphorylation, thereby limiting the p53 functions in PTEN-/- CRC cells. MDM2 inhibition in turn activated p53 in CRC, particularly in PTEN-/- CRC cells. The synthetic lethal effect of MDM2 inhibitor was largely dependent on p53, because p53 silenced cells or cells lacking p53 failed to exhibit synthetic lethality in PTEN-deficient cells. We further showed that MDM2 inhibition led to the p53-dependent reversal of Bcl2-Bax ratio, which contributed to mitochondria-mediated apoptotic cell death in PTEN-deficient CRC. This study suggests that pharmacological targeting of MDM2 could be a potential therapeutic strategy for PTEN-deficient CRC.

Giant enhancement of acoustic and fluorescence emission from an off-axis reflective femtosecond laser filamentation system.

Femtosecond laser filamentation propagating tens of meters to several kilometers with high intensity in the atmosphere has been demonstrated as a powerful tool for remote sensing. In contrast to the refractive systems, the reflective optical systems possess a variety of advantages including broad bandwidth, large aperture, light weight and low energy loss. However, astigmatic aberration is inevitably introduced by off-axis reflective mirrors. It can greatly affect the filament quality, which is critical for exciting and detecting the fluorescence of target molecules. Here we elaborately design a free-form phase plate to correct the astigmatism in off-axis reflective optical systems. It is demonstrated that the free-form surface exhibits excellent performance, significantly reducing the astigmatic difference from 44 cm to 4 cm and increasing the maximum acoustic intensity by a factor of 53. In addition, extremely strong nitrogen fluorescence spectra have been detected. These results indicate that the free-form phase plate can effectively compensate for astigmatic aberration in off-axis reflective system, providing a guiding significance for the optimal control of filamentation and remote sensing.

TRIM59 guards ER proteostasis and prevents Bortezomib-mediated colorectal cancer (CRC) cells' killing.

The endoplasmic reticulum (ER) is a critical organelle that preserves the protein homeostasis of cells. Under various stress conditions, cells evolve a degree of capacity to maintain ER proteostasis, which is usually augmented in tumor cells, including colorectal cancer (CRC) cells, to bolster their survival and resistance to apoptosis. Bortezomib (BTZ) is a promising drug used in CRC treatment; however, its main limitation result from drug resistance. Here, we identified the role of tripartite motif-containing protein 59 (TRIM59)-a protein localized on the ER membrane- in the prevention of BTZ-mediated CRC killing. Depletion of TRIM59 is associated with the enhancement of ER stress and a remarkable increase in unfolded protein response (UPR) signaling. Besides, TRIM59 strengthens ER-associated degradation (ERAD) and alleviates the generation of ROS. Of note, TRIM59 knockdown synergizes with the anti-cancer effect of BTZ both in vitro and in vivo. Our findings revealed a role for TRIM59 in the ER by guarding ER proteostasis and represents a novel therapeutic target of CRC.

Investigation of Focusing Properties on Astigmatic Gaussian Beams in Nonlinear Medium.

Ultra-short laser filamentation has been intensively studied due to its unique optical properties for applications in the field of remote sensing and detection. Although significant progress has been made, the quality of the laser beam still suffers from various optical aberrations during long-range transmission. Astigmatism is a typical off-axis aberration that is often encountered in the off-axis optical systems. An effective method needs to be proposed to suppress the astigmatism of the beam during filamentation. Herein, we numerically investigated the impact of the nonlinear effects on the focusing properties of the astigmatic Gaussian beams in air and obtained similar results in the experiment. As the single pulse energy increases, the maximum on-axis intensity gradually shifted from the sagittal focus to the tangential focus and the foci moved forward simultaneously. Moreover, the astigmatism could be suppressed effectively with the enhancement of the nonlinear effects, that is, the astigmatic difference and the degree of beam distortion were both reduced. Through this approach, the acoustic intensity of the filament (located at the tangential focal point) increased by a factor of 22.8. Our work paves a solid step toward the practical applications of the astigmatism beam as the nonlinear lidar.

Beam Wander Restrained by Nonlinearity of Femtosecond Laser Filament in Air.

The filamentation process under atmospheric turbulence is critical to its remote-sensing application. The effects of turbulence intensity and location on the spatial distribution of femtosecond laser filaments in the air were studied. The experimental results show that the nonlinear effect of the filament can restrain the beam wander. When the turbulence intensity was 3.31×10−13 cm−2/3, the mean deviation of the wander of the filament center was only 27% of that of the linear transmitted beam. The change in turbulence location would lead to a change in the standard deviation of the beam centroid drift. Results also show that the filament length would be shortened, and that the filament would end up earlier in a turbulent environment. Since the filamentation-based LIDAR has been highly expected as an evolution multitrace pollutant remote-sensing technique, the study promotes our understanding of how turbulence influences filamentation and advances atmospheric remote sensing by applying a filament.

Aurora kinase A inhibition induces synthetic lethality in SMAD4-deficient colorectal cancer cells via spindle assembly checkpoint activation.

SMAD4 loss-of-function mutations have been frequently observed in colorectal cancer (CRC) and are recognized as a drug target for therapeutic exploitation. In this study, we performed a synthetic lethal drug screening with SMAD4-isogenic CRC cells and found that aurora kinase A (AURKA) inhibition is synthetic lethal with SMAD4 loss. Inhibition of AURKA selectively inhibited the growth of SMAD4-/- CRC in vitro and in vivo. Mechanistically, SMAD4 negatively regulated AURKA level, resulting in the significant elevation of AURKA in SMAD4-/- CRC cells. Inhibition of AURKA induced G2/M cell cycle delay in SMAD4+/+ CRC cells, but induced apoptosis in SMAD4-/- CRC cells. We further observed that a high level of AURKA in SMAD4-/- CRC cells led to abnormal mitotic spindles, leading to cellular aneuploidy. Moreover, SMAD4-/- CRC cells expressed high levels of spindle assembly checkpoint (SAC) proteins, suggesting the hyperactivation of SAC. The silencing of key SAC proteins significantly rescued the AURKA inhibition-induced cell death in SMAD4-/- cells, suggesting that SMAD4-/- CRC cells are hyper-dependent on AURKA activity for mitotic exit and survival during SAC hyperactivation. This study presents a unique synthetic lethal interaction between SMAD4 and AURKA and suggests that AURKA could be a potential drug target in SMAD4-deficient CRC.

Natural products targeting cancer cell dependency.

Precision cancer medicine is a tailored treatment approach for individual cancer patients with different genomic characteristics. Mutated or hyperactive oncogenes have served as main drug targets in current precision cancer medicine, while defective or inactivated tumor suppressors in general have not been considered as druggable targets. Synthetic lethality is one of very few approaches that enable to target defective tumor suppressors with pharmacological agents. Synthetic lethality exploits cancer cell dependency on a protein or pathway, which arises when the function of a tumor suppressor is defective. This approach has been proven to be effective in clinical settings since the successful clinical introduction of BRCA-PARP synthetic lethality for the treatment of breast and ovarian cancer with defective BRCA. Subsequently, large-scale screenings with RNAi, CRISPR/Cas9-sgRNAs, and chemical libraries have been applied to identify synthetic lethal partners of tumor suppressors. Natural products are an important source for the discovery of pharmacologically active small molecules. However, little effort has been made in the discovery of synthetic lethal small molecules from natural products. This review introduces recent advances in the discovery of natural products targeting cancer cell dependency and discusses potentials of natural products in the precision cancer medicine.

Aurora kinase A, a synthetic lethal target for precision cancer medicine.

Recent advances in high-throughput sequencing technologies and data science have facilitated the development of precision medicine to treat cancer patients. Synthetic lethality is one of the core methodologies employed in precision cancer medicine. Synthetic lethality describes the phenomenon of the interplay between two genes in which deficiency of a single gene does not abolish cell viability but combined deficiency of two genes leads to cell death. In cancer treatment, synthetic lethality is leveraged to exploit the dependency of cancer cells on a pathway that is essential for cell survival when a tumor suppressor is mutated. This approach enables pharmacological targeting of mutant tumor suppressors that are theoretically undruggable. Successful clinical introduction of BRCA-PARP synthetic lethality in cancer treatment led to additional discoveries of novel synthetic lethal partners of other tumor suppressors, including p53, PTEN, and RB1, using high-throughput screening. Recent work has highlighted aurora kinase A (AURKA) as a synthetic lethal partner of multiple tumor suppressors. AURKA is a serine/threonine kinase involved in a number of central biological processes, such as the G2/M transition, mitotic spindle assembly, and DNA replication. This review introduces synthetic lethal interactions between AURKA and its tumor suppressor partners and discusses the potential of AURKA inhibitors in precision cancer medicine.

TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway.

Tumor cells often exhibit augmented capacity to maintain endoplasmic reticulum (ER) homeostasis under adverse conditions, yet the underlying mechanisms are not well defined. Here, through the evaluation of all human TRIM proteins, we find that TRIM25 is significantly induced upon ER stress. Upregulation of TRIM25 ameliorates oxidative stress, promotes ER-associated degradation (ERAD), and reduces IRE1 signaling in the UPR pathway. In contrast, depletion of TRIM25 leads to ER stress and attenuates tumor cell growth in vitro and in vivo. Mechanistically, TRIM25 directly targets Keap1 by ubiquitination and degradation. This leads to Nrf2 activation, which bolsters anti-oxidant defense and cell survival. TRIM25 expression is positively associated with Nrf2 expression and negatively with Keap1 expression in hepatocellular carcinoma (HCC) xenografts and specimens. Moreover, high TRIM25 expression correlates with poor patient survival in HCC. These findings reveal TRIM25 as a regulator of ER homeostasis and a potential target for tumor therapy.