Cholesterol biogenesis is a PTEN-dependent actionable node for the treatment of endocrine therapy-refractory cancers.

PTEN and PIK3CA mutations are the most prevalent PI3K pathway alterations in prostate, breast, colorectal, and endometrial cancers. p110ß becomes the prominent PI3K isoform upon PTEN loss. In this study, we aimed to understand the molecular mechanisms of PI3K dependence in the absence of PTEN. Using online bioinformatical tools, we examined two publicly available microarray datasets with aberrant PI3K activation. We found that the rate-limiting enzyme of cholesterol biogenesis, SQLE, was significantly upregulated in p110ß-hyperactivated or PTEN-deficient mouse prostate tumors. Concomitantly, the expression of cholesterol biosynthesis pathway enzymes was directly correlated with PI3K activation status in microarray datasets and diminished upon PTEN re-expression in PTEN-null prostate cancer cells. Particularly, PTEN re-expression decreased SQLE protein levels in PTEN-deficient prostate cancer cells. We performed targeted metabolomics and detected reduced levels of cholesteryl esters as well as free cholesterol upon PTEN re-expression. Notably, PTEN-null prostate and breast cancer cell lines were more sensitive to pharmacological intervention with the cholesterol pathway than PTEN-replete cancer cells. Since steroid hormones use sterols as structural precursors, we studied whether cholesterol biosynthesis may be a metabolic vulnerability that enhances antihormone therapy in PTEN-null castration-resistant prostate cancer cells. Coinhibition of cholesterol biosynthesis and the androgen receptor enhanced their sensitivity. Moreover, PTEN suppression in endocrine therapy-resistant luminal-A breast cancer cells leads to an increase in SQLE expression and a corresponding sensitization to the inhibition of cholesterol synthesis. According to our data, targeting cholesterol biosynthesis in combination with the hormone receptor signaling axis can potentially treat hormone-resistant prostate and breast cancers.

Overview and Challenges of Large-Scale Cultivation of Photosynthetic Microalgae and Cyanobacteria.

Microalgae and cyanobacteria are diverse groups of organisms with great potential to benefit societies across the world. These organisms are currently used in food, feed, pharmaceutical and cosmetic industries. In addition, a variety of novel compounds are being isolated. Commercial production of photosynthetic microalgae and cyanobacteria requires cultivation on a large scale with high throughput. However, scaling up production from lab-based systems to large-scale systems is a complex and potentially costly endeavor. In this review, we summarise all aspects of large-scale cultivation, including aims of cultivation, species selection, types of cultivation (ponds, photobioreactors, and biofilms), water and nutrient sources, temperature, light and mixing, monitoring, contamination, harvesting strategies, and potential environmental risks. Importantly, we also present practical recommendations and discuss challenges of profitable large-scale systems associated with economical design, effective operation and maintenance, automation, and shortage of experienced phycologists.

Biological removal of benzalkonium chlorides from wastewater by immobilized cells of Pseudomonas sp. BIOMIG1 in an up-flow packed bed reactor.

Quaternary ammonium compounds (QACs) are active ingredients of many disinfectants used against SARS-CoV-2 to control the transmission of the virus through human-contact surfaces. As a result, QAC consumption has increased more than twice during the pandemic. Consequently, the concentration of QACs in wastewater and receiving environments may increase. Due to their antimicrobial activity, high levels of QACs in wastewater may cause malfunctioning of biological treatment systems resulting in inadequate treatment of wastewater. In this study, a biocatalyst was produced by entrapping Pseudomonas sp. BIOMIG1 capable of degrading QACs in calcium alginate. Bioactive 3-mm alginate beads degraded benzalkonium chlorides (BACs), a group of QACs, with a rate of 0.47 µM-BACs/h in shake flasks. A bench-scale continuous up-flow reactor packed with BIOMIG1-beads was operated over one and a half months with either synthetic wastewater or secondary effluent containing 2-20 µM BACs at an empty bed contact time (EBCT) ranging between 0.6 and 4.7 h. Almost complete BAC removal was achieved from synthetic and real wastewater at and above 1.2 h EBCT without aeration and effluent recirculation. The microbial community in beads dominantly composed of BIOMIG1 with trace number of Achromobacter spp. after the operation of the reactor with the real wastewater, suggesting that BIOMIG1 over-competed native wastewater bacteria during the operation. This reactor system offers a low cost and robust treatment of QACs in wastewater. It can be integrated to conventional treatment systems for efficient removal of QACs from the wastewater, especially during the pandemic period.