Thanigaivelan Kanagasabai

Resistance to androgen receptor (AR)–targeted therapies for prostate cancer (PCa) is characteristic of an aggressive subtype called castration-resistant prostate cancer (CRPC) and is often associated with tumor relapse. Both relapse and poor prognosis in patients with CRPC are associated with increased abundance of the E3 ubiquitin ligase SKP2. Therefore, we investigated the therapeutic potential of combined inhibition of AR and SKP2 for CRPC. We found that combined targeting of AR and SKP2 with small-molecule inhibitors decreased proliferation in two CRPC cell lines in culture and in xenografts in humanized mice. Furthermore, combined therapy in mice markedly decreased the growth of Pten/Trp53 double-knockout tumors, a particularly invasive model of CRPC, whereas disruption of either AR or SKP2 alone only modestly suppressed their growth. Mechanistically, the inhibition of SKP2 in CRPC cells induced autophagy-dependent apoptosis and promoted luminal-associated phenotypes, which promoted responsiveness to AR-targeted therapy. These effects were further enhanced by coinhibition of AR and were not induced by the AR inhibitor alone. Our findings indicate that targeting both AR and SKP2 signaling pathways is necessary to treat CRPC.

Polycyclic aromatic hydrocarbons (PAHs), one of the major environmental pollutants, produced from incomplete combustion of materials like coal, oil, gas, wood, and charbroiled meat, that contaminate the air, soil, and water, necessitating urgent remediation. Understanding the metabolic pathways for PAHs degradation is crucial to preventing environmental damage and health issues. Biological methods are gaining increasing interest due to their cost‐effectiveness and environmental friendliness. These methods are particularly suitable for remediating PAHs contamination and mitigating associated risks. The paper also outlines the processes for biodegrading PAHs, emphasizing the function of Pseudomonas spp., a kind of bacterium recognized for its capacity to degrade PAHs. To eliminate PAHs from the environment and reduce threats to human health and the environment, Pseudomonas spp. is essential. Understanding the mechanism of PAH breakdown by means of microbes could lead to effective clean‐up strategies. The review highlights the enzymatic capabilities, adaptability, and genetic versatility of the genes like nah and phn of Pseudomonas spp., which are involved in PAHs degradation pathways. Scientific evidence supports using Pseudomonas spp. as biocatalysts for PAHs clean‐up, offering cost‐effective and eco‐friendly solutions.

Brain pathological changes impair cognition early in disease etiology. There is an urgent need to understand aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2 is a mitochondrial-resident protein regulating Ca²⁺ fluxes to and from mitochondria impacting overall health. We previously reported that Tusc2^−/− female mice develop chronic inflammation and age prematurely, causing age- and sex-dependent spatial memory deficits at 5 months old. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in 4-month-old mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2^−/− female mice demonstrated a pro-inflammatory increase in astrocytes, expression of IFN-γ in CD4⁺ T cells and Granzyme-B in CD8⁺T cells. We also found fewer FOXP3⁺ T-regulatory cells and Ly49G⁺ NK and Ly49G⁺ NKT cells in female Tusc2^−/− brains, suggesting a dampened anti-inflammatory response. Moreover, Tusc2^−/− hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca²⁺ dynamics. Overall, the data suggest that dysregulation of Ca²⁺-dependent processes and a heightened pro-inflammatory brain microenvironment in Tusc2^−/− mice could underlie cognitive impairment. Thus, strategies to modulate the mitochondrial Tusc2- and Ca²⁺- signaling pathways in the brain should be explored to improve cognitive health.

Brain pathological changes impair cognition early in disease etiology. There is an urgent need for understanding aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2, also named Fus1, is a mitochondrial-resident protein regulating Ca2+ fluxes to and from mitochondria impacting overall health. We reported that Tusc2-/- female mice develop chronic inflammation and age prematurely, causing age- and gender-dependent spatial memory deficits at 5 m.o. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2-/- female mice demonstrated proinflammatory increase in astrocytes, IFN-γ expression in CD4+T cells and Granzyme-B in CD8+T cells. We also found fewer FOXP3+ T-regulatory cells and Ly49G+ NK and Ly49G+ NKT cells in female Tusc2-/- brain, suggesting a weakened anti-inflammatory response. Moreover, Tusc2-/- hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca2+ dynamics. Overall, data suggest that dysregulation of Ca2+-dependent processes and proinflammatory brain microenvironment heighten in Tusc2-/- mice could underlie cognitive impairment. Thus, strategies to modulate the brain’s Tusc2-, Ca2+, and mitochondria-dependent pathways should be explored to improve cognitive health.

Background: Prostate cancer (PCa) is the second‐leading cause of cancer mortalities in the United States and is the most commonly diagnosed malignancy in men. While androgen deprivation therapy (ADT) is the first‐line treatment option to initial responses, most PCa patients invariably develop castration‐resistant PCa (CRPC). Therefore, novel and effective treatment strategies are needed. The goal of this study was to evaluate the anticancer effects of the combination of two small molecule inhibitors, SZL‐P1‐41 (SKP2 inhibitor) and PBIT (KDM5B inhibitor), on PCa suppression and to delineate the underlying molecular mechanisms.Methods: Human CRPC cell lines, C4‐2B and PC3 cells, were treated with small molecular inhibitors alone or in combination, to assess effects on cell proliferation, migration, senescence, and apoptosis.Results: SKP2 and KDM5B showed an inverse regulation at the translational level in PCa cells. Cells deficient in SKP2 showed an increase in KDM5B protein level, compared to that in cells expressing SKP2. By contrast, cells deficient in KDM5B showed an increase in SKP2 protein level, compared to that in cells with KDM5B intact. The stability of SKP2 protein was prolonged in KDM5B depleted cells as measured by cycloheximide chase assay. Cells deficient in KDM5B were more vulnerable to SKP2 inhibition, showing a twofold greater reduction in proliferation compared to cells with KDM5B intact (p < 0.05). More importantly, combined inhibition of KDM5B and SKP2 significantly decreased proliferation and migration of PCa cells as compared to untreated controls (p < 0.005). Mechanistically, combined inhibition of KDM5B and SKP2 in PCa cells abrogated AKT activation, resulting in an induction of both cellular senescence and apoptosis, which was measured via Western blot analysis and senescence‐associated β‐galactosidase (SA‐β‐Gal) staining.Conclusions: Combined inhibition of KDM5B and SKP2 was more effective at inhibiting proliferation and migration of CRPC cells, and this regimen would be an ideal therapeutic approach of controlling CRPC malignancy.

Background: Defects in apoptosis regulation are one of the classical features of cancer cells, often associated with more aggressiveness and failure to therapeutic options. We investigated the combinatorial antitumor effects of a natural product, physachenolide C (PCC) and bortezomib, in KRAS^mut/P53^mut lung cancer cells and xenograft mice models. Methods: The in vitro anticancer effects of the bortezomib and PCC combination were investigated using cell viability, migration, and invasion assays in 344SQ, H23, and H358 cell lines. Furthermore, the effects of combination treatment on the critical parameters of cellular metabolism, including extracellular acidification rate (ECAR) and mitochondrial oxidative phosphorylation based on the oxygen consumption rate of cancer cells were assessed using Seahorse assay. Finally, the antitumor effect of the bortezomib (1 mg/kg) and PCC (10 mg/kg) combination was evaluated using xenograft mice models. Results: Our data showed that the bortezomib–PCC combination was more effective in reducing the viability of lung cancer cells in comparison with the individual treatments. Similarly, the combination treatment showed a significant inhibition of cell migration and invasion of cancer cells. Additionally, the key anti-apoptotic protein c-FLIP was significantly inhibited along with a substantial reduction in the key parameters of cellular metabolism in cancer cells. Notably, the bortezomib or PCC inhibited the tumor growth compared to the control group, the tumor growth inhibition was much more effective when bortezomib was combined with PCC in tumor xenograft mice models. Conclusion: These findings demonstrate that PCC sensitizes cancer cells to bortezomib, potentially improving the antitumor effects against KRAS^mut/P53^mut lung cancer cells, with an enhanced efficacy of combination treatments without causing significant side effects.

Screening for sensitizers of cancer cells to TRAIL-mediated apoptosis identified a natural product of the 17β-hydroxywithanolide (17-BHW) class, physachenolide C (PCC), as a promising hit. In this study, we show that PCC was also able to sensitize melanoma and renal carcinoma cells to apoptosis in response not only to TRAIL, but also to the synthetic polynucleotide poly I:C, a viral mimetic and immune activator, by reducing levels of antiapoptotic proteins cFLIP and Livin. Both death receptor and TLR3 signaling elicited subsequent increased assembly of a proapoptotic ripoptosome signaling complex. Administration of a combination of PCC and poly I:C in human M14 melanoma xenograft and a syngeneic B16 melanoma model provided significant therapeutic benefit as compared with individual agents. In addition, PCC enhanced melanoma cell death in response to activated human T cells in vitro and in vivo in a death ligand–dependent manner. Biochemical mechanism-of-action studies established bromo and extraterminal domain (BET) proteins as major cellular targets of PCC. Thus, by targeting of BET proteins to reduce antiapoptotic proteins and enhance caspase-8–dependent apoptosis of cancer cells, PCC represents a unique agent that can potentially be used in combination with various immunotherapeutic approaches to promote tumor regression and improve outcome.Significance: These findings demonstrate that PCC selectively sensitizes cancer cells to immune-mediated cell death, potentially improving the efficacy of cancer immunotherapies.