CyclinG1 Amplification Enhances Aurora Kinase Inhibitor-Induced Polyploid Resistance and Inhibition of Bcl-2 Pathway Reverses the Resistance.

BACKGROUND/AIMS: CyclinG1 (CycG1) is frequently overexpressed in solid tumors and overexpression of CycG1 promotes cell survival upon paclitaxel exposure by inducing polyploidy. Whether and how CycG1 regulates polyploidization caused by small molecular targeted inhibitors remains unclear. METHODS: Immunohistochemistry and immunoblotting were utilized to examine protein expression. Cell proliferation was measured by ATPlite assay, and cell cycle distribution and apoptosis were measured by flow cytometry and/or DNA fragmentation assays. RESULTS: Overexpression of CycG1 in breast cancer cells caused apoptosis-resistant polyploidy upon treatment with Aurora kinase inhibitor, ZM447439 (ZM). Addition of ABT-263, a small-molecule BH3 mimetic, to ZM, produced a synergistic loss of cell viability with greater sustained tumor growth inhibition in breast cancer cell lines. Decrease of Mcl-1 and increase of NOXA caused by ZM treatment, were responsible for the synergy. Furthermore, CycG1 was highly expressed in Triple-Negative-Breast-Cancer patients treated with paclitaxel and was paralleled by decreased cell survival. CONCLUSION: CycG1 is a crucial factor in ZM-induced polyploidy resistance, and ABT-263/ZM combination hold therapeutic utility in the CycG1-amplified subset of breast cancer and CycG1, thus, is a promising target in breast cancer.

The ceramide synthase (CERS/LASS) family: Functions involved in cancer progression.

INTRODUCTION: Ceramide synthases (CERSes) are also known longevity assurance (LASS) genes. CERSes play important roles in the regulation of cancer progression. The CERS family is expressed in a variety of human tumours and is involved in tumorigenesis. They are closely associated with the progression of liver, breast, cervical, ovarian, colorectal, head and neck squamous cell, gastric, lung, prostate, oesophageal, pancreatic and blood cancers. CERSes play diverse and important roles in the regulation of cell survival, proliferation, apoptosis, migration, invasion, and drug resistance. The differential expression of CERSes in tumour and nontumour cells and survival analysis of cancer patients suggest that some CERSes could be used as potential prognostic markers. They are also important potential targets for cancer therapy. METHODS: In this review, we summarize the available evidence on the inhibitory or promotive roles of CERSes in the progression of many cancers. Furthermore, we summarize the identified upstream and downstream molecular mechanisms that may regulate the function of CERSes in cancer settings.

BTN3A3 inhibits clear cell renal cell carcinoma progression by regulating the ROS/MAPK pathway via interacting with RPS3A.

Butyrophilin subfamily 3 member A3 (BTN3A3) is a member of the immunoglobulin superfamily and functions as a tumor suppressor in multiple cancer types. Our study has revealed that in clear cell renal cell carcinoma (ccRCC), patients who express high levels of BTN3A3 experience longer survival times than those with lower expression. Further, we have observed that BTN3A3 inhibits the proliferation, migration, and invasion of ccRCC cells. Through the utilization of an immunoprecipitation assay followed by mass spectrometry, we have discovered that BTN3A3 binds directly to RPS3A. Knockdown of BTN3A3 led to increased cell proliferation, migration, and invasion. However, this effect was significantly reduced when RPS3A was simultaneously overexpressed. Previous reports have demonstrated that RPS3A positively regulates mitochondrial function and reactive oxygen species (ROS) levels. Our study has shown that overexpression of both BTN3A3 and RPS3A can increase cellular oxygen consumption rate (OCR) and ROS levels. Furthermore, we have observed that the addition of H2O2 can reverse the effects of BTN3A3 knockdown on cell proliferation and migration by increasing the cellular ROS level. ROS play a crucial role in regulating the MAPK pathway and tumor cell growth. To further explore this relationship, we examined RNA-Seq and immunoblotting data and found that BTN3A3 can negatively regulate the degree of activation of the MAPK signaling pathway. This finding suggests that the BTN3A3/RPS3A complex may regulate ccRCC progression by modulating MAPK pathways. Therefore, BTN3A3 could serve as both a prognostic marker and a potential therapeutic target for ccRCC patients.

BTN3A3 inhibits the proliferation, migration and invasion of ovarian cancer cells by regulating ERK1/2 phosphorylation.

Butyrophilin Subfamily 3 Member A3 (BTN3A3) is a type I transmembrane protein belonging to the immunoglobulin (Ig) superfamily, which is expressed in many cancers. Clinical data show that ovarian cancer patients with high expression of BTN3A3 have a longer survival time, but the mechanism of BTN3A3 in the occurrence and progression of ovarian cancer is still unclear. Here, we found that BTN3A3 knockdown can promote the proliferation, migration and invasion of ovarian cancer cells, while overexpression of BTN3A3 can inhibit the proliferation, migration and invasion of ovarian cancer cells. We analyzed the immunoprecipitated BTN3A3 complex by mass spectrometry and found that BTN3A3 binds to FGF2, and the overexpression of BTN3A3 leads to a decrease in the protein level of FGF2, which in turn leads to a decrease in the level of phosphorylation of ERK1/2. By increasing the protein level of FGF2, it was found that the level of ERK1/2 phosphorylation also increased. Finally, the cancer promotion phenomenon caused by BTN3A3 knockdown can be improved by using ERK1/2 inhibitor SCH772984. To sum up, BTN3A3 interacts with FGF2, which inhibits FGF2/ERK1/2 axis and ultimately inhibits the proliferation, migration and invasion of ovarian cancer cells. Our results suggest that BTN3A3 may be a prognostic marker and a potential therapeutic target for ovarian cancer.

Prognostic and Therapeutic Significance of BTN3A Proteins in Tumors.

The Butyrophilin 3A (BTN3A) family is a type I transmembrane protein belonging to the immunoglobulin (Ig) superfamily. The family contains three members: BTN3A1, BTN3A2 and BTN3A3, which share 95% homology in the extracellular domain. The expression of BTN3A family members is different in different types of tumors, which plays an important role in tumor prognosis. Among them, there are many studies on tumor immunity of BTN3A1, which shows that it is essential for the activation of Vγ9Vδ2 T cells, while BTN3A3 is expected to become a potential therapeutic target for breast cancer. Recent studies have shown that the BTN3A family is closely related to the occurrence and development of tumors. Now the BTN3A family has become one of the research hotspots and is expected to become new tumor prediction and treatment targets.

Aurora-A/ERK1/2/mTOR axis promotes tumor progression in triple-negative breast cancer and dual-targeting Aurora-A/mTOR shows synthetic lethality.

Triple-negative breast cancer (TNBC), defined as a tumor subtype that lacks ER, PR, and HER2, shows a poor prognosis due to its aggressive tumor biology and limited treatment options. Deregulation of Aurora kinase A (Aur-A), a member of the mitotic serine/threonine Aurora kinase family, and overactivation of the mTOR pathway commonly occur in multiple cancer types. We previously found that Aur-A activated the mTOR pathway and inhibited autophagy activity in breast cancer cell models. Whether and how Aur-A regulates mTOR in TNBC are still unclear. Here, we found that Aur-A and p-mTOR are highly expressed and positively associated with each other in TNBC cells and tissues. Inhibition or knockdown of Aur-A decreased p-mTOR and suppressed cell proliferation and migration, whereas overexpression of Aur-A increased p-mTOR levels and promoted cell proliferation and migration, which was significantly abrogated by simultaneous silencing of mTOR. Intriguingly, overexpression of Aur-A enhanced the expression of p-mTOR and p-ERK1/2, and silencing or inhibition of ERK1/2 blocked Aur-A-induced p-mTOR. However, silencing or inhibition of mTOR failed to reverse Aur-A-induced ERK1/2, indicating that Aur-A/ERK1/2/mTOR forms an oncogenic cascade in TNBC. We finally found that double inhibition of Aur-A and mTOR showed significant synergistic effects in TNBC cell lines and a xenograft model, indicating that Aur-A and mTOR are potential therapeutic targets in the TNBC subtype.

Molecular Evolution of GDP-D-Mannose Epimerase (GME), a Key Gene in Plant Ascorbic Acid Biosynthesis.

The widespread ascorbic acid (AsA) plays a vital role in plant development and abiotic stress tolerance, but AsA concentration varies greatly among different plants. GDP-D-mannose epimerase (GME), which catalyzes GDP-D-mannose to GDP-L-galactose or GDP-L-gulose, is a key enzyme in plant AsA biosynthesis pathway. Functions and expression patterns of GME have been well studied in previous works, however, little information is known about the evolutionary patterns of the gene. In this study, GME gene structure, corresponding conserved protein motifs and evolutionary relationships were systematically analyzed. A total of 111 GME gene sequences were retrieved from 59 plant genomes, which representing almost all the major lineages of Viridiplantae: dicotyledons, monocotyledons, gymnosperms, pteridophytes, bryophytes, and chlorophytes. Results showed that homologs of GME were widely present in Viridiplantae. GME gene structures were conservative in higher plants, while varied greatly in the basal subgroups of the phylogeny including lycophytes, bryophytes, and chlorophytes, suggesting GME gene structure might have undergone severe differentiation at lower plant and then gradually fixed as plant evolution. The basic motifs of GME were strongly conserved throughout Viridiplantae, suggesting the conserved function of the protein. Molecular evolution analysis showed that strong purifying selection was the predominant force in the evolution of GME. A few branches and sites under episodic diversifying selection were identified and most of the branches located in the subgroup of chlorphytes, indicating episodic diversifying selection at a few branches and sites may play a role in the evolution of GME and diversifying selection may have occurred at the early stage of Viridiplantae. Our results provide novel insights into functional conservation and the evolution of GME.