Search Results (179)

Mitochondria are dynamic organelles that undergo repeated fusion and fission. We studied how the distribution and shape of mitochondria change during Drosophila spermatogenesis and whether factors that regulate their dynamics are necessary for these changes. Unlike the shortened mitochondria seen in mitosis, an interconnected network of elongated mitochondria forms before meiosis and is maintained during meiotic divisions. Mitochondria are evenly divided into daughter cells, relying on microtubules and F-actin. To explore the role of mitochondrial network structure in cell growth and meiosis, we depleted the mitochondrial fusion factors Opa1 and Marf and the morphology proteins Letm1 and EndoB in spermatocytes. This knockdown led to inhibited cell growth and failed meiosis. As a result, the spermatocytes differentiated into spermatids without completing meiosis. The knockdown also inhibited the cytoplasmic and nuclear accumulation of Cyclin B before meiosis, and Cdk1 was not fully activated at the onset of meiosis. Notably, ectopic overexpression of Cyclin B partially rescued the failure of meiosis. Many spermatids from the spermatocytes subjected to the knockdowns contained multiple smaller nuclei and abnormally shaped Nebenkerns. These findings suggest that mitochondrial network structure, maintained by fusion and morphology factors, is essential for meiosis progression and Nebenkern formation in Drosophila spermatogenesis. Full article

Promising protein targets are observed to play a role in multiple pathways across a variety of diseases, such as the regulation of immune responses, cell cycle, senescence, and DNA repair. The oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) can coordinate all these cell characteristics predominately by inhibiting the activity of the serine threonine protein phosphatase 2A (PP2A). CIP2A directly interacts with PP2A and other proteins, such as the DNA damage protein topoisomerase II-binding protein 1, to regulate signal transduction. CIP2A is overexpressed in many human cancers, including small and non-small cell lung cancers. High CIP2A expression in lung cancer correlates with poor prognosis, increased tumor proliferation, and resistance to targeted therapies or chemotherapy. Interestingly, CIP2A expression or signaling is also observed in several non-cancerous pulmonary diseases, such as chronic obstructive pulmonary disease. CIP2A can determine whether DNA-damaged cells enter mitosis and can mediate whether DNA repair occurs. CIP2A is also a regulator of inflammation and possibly fibrotic responses. Its functions are linked to altered NFκB activation and TNFα, IL-1β, IL-4, IL-6, IL-10, IL-13, and TGFβ signaling. This review outlines the possible impact of CIP2A-mediated signaling in pulmonary diseases, the processes that regulate CIP2A responses, CIP2A-dependent pathways, and potential therapeutic strategies targeting CIP2A. Substantial medicinal chemistry efforts are underway to develop therapeutics aimed at modulating CIP2A activity. The development of specific inhibitors of CIP2A that selectively target its expression or protein stability could improve our understanding of CIP2A’s function in pulmonary diseases. Full article

Kinesin spindle protein (KSP), also known as KIF11, is a member of the kinesin superfamily of motor proteins that plays a pivotal role in mitosis by regulating spindle assembly, chromosome alignment, and segregation. Its motor activity, which is essential for the proper organization of microtubules during mitosis, is crucial for maintaining genomic stability. KSP overexpression has been observed in several cancer types, where it promotes uncontrolled cell proliferation, making it a promising target for cancer therapy. This review provides a comprehensive analysis of the molecular mechanisms underlying KSP function, including its structural features, ATPase activity, and interactions with other mitotic proteins. Additionally, we review the regulation of KSP through post-translational modifications, such as phosphorylation, as well as the therapeutic strategies currently being explored to inhibit its activity in cancer treatment. Full article

Cyanobacterial blooms in aquatic ecosystems are a major global environmental concern. While the mutagenic and mitosis-disrupting properties of isolated cyanobacterial toxins are well documented, evidence of cytogenotoxic effects resulting from cyanobacterial blooms in natural aquatic ecosystems remains limited. In this study, water genotoxicity was evaluated in microcosms simulating cyanobacterial blooms of varying abundance. In microcosms with initially high cyanobacterial abundances (4.6 × 10⁷ and 2.2 × 10⁷ cells L⁻¹) and biomass (58 mg L⁻¹ and 20 mg L⁻¹), significant toxic, cytotoxic, mitosis-disrupting, and mutagenic effects were observed: root elongation was inhibited by up to 49.6% (Day 1), the mitotic index decreased by ~33% (Treatment I, Day 42) vs. Control, and total chromosomal aberrations and lagging chromosomes increased by ~2.5-fold on Day 1 (Treatment I) and ~4.7-fold on Day 42 (Treatment I) vs. Control; micronuclei increased ~10-fold on Day 42 in Treatment I and II. In microcosms with lower cyanobacterial abundance (1.2 × 10⁷ cells L⁻¹) and biomass (9 mg L⁻¹), significant reductions were observed only in root growth and in the mitotic index compared with Control. Future research should aim to identify a broader spectrum of cyanobacterial toxins and to investigate their environmental fate and persistence in aquatic ecosystems, particularly since genotoxic effects were detected even during the post-bloom period: on Day 42 extracellular microcystins in water were <LOQ in Treatments I and III (and 0.025 µg L⁻¹ in Treatment II), yet chromosome lagging and micronuclei remained elevated. The observed genotoxicity associated with cyanobacterial metabolites underscores the need for thorough risk assessments of cyanobacterial blooms in aquatic environments. Full article

Background/Objectives: HNSCC is a highly aggressive malignancy marked by the dysregulation of the cell cycle. In HPV⁻ HNSCC, mutations in the CDKN2A gene frequently result in the loss of the p16 protein, a key inhibitor of the cyclin D1/CDK4/6 complex. This loss results in unchecked G1/S phase progression. The CDK4/6 inhibitor palbociclib has shown therapeutic potential in HPV⁻ HNSCC by inducing G1 phase arrest and reducing cell viability. In this study, we investigated the molecular mechanisms by which palbociclib affects cell viability in HPV⁻ HNSCC. Methods: Four HPV⁻ HNSCC cell lines were treated with palbociclib, and RNA sequencing was performed to assess changes in gene expression. Cell viability was measured using the MTT assay. To further investigate protein localization, interactions, and function, we used immunofluorescence staining, co-immunoprecipitation, small molecule inhibitors, and siRNA-mediated knockdown. Results: We demonstrate that palbociclib downregulates survivin, a protein that plays dual roles in mitosis and apoptosis, thereby inhibiting cell proliferation. We also found that survivin is overexpressed in HPV⁻ HNSCC. Inhibiting survivin dimerization using the compound LQZ-7i significantly reduces cell viability and promotes its export from the nucleus to the cytoplasm. Additionally, we identified USP1, a deubiquitinase, as both a downstream target of CDK4/6 and a key regulator of survivin stability. Inhibiting USP1 activity or silencing its expression significantly reduces survivin levels. Conclusions: Our findings highlight survivin as a critical mediator of cell proliferation in HPV⁻ HNSCC and suggest that targeting the CDK4/6-USP1-survivin axis may offer a promising therapeutic strategy. Full article

Aurora kinase B (AURKB), a serine/threonine protein kinase, is essential for accurate chromosome segregation and cytokinesis during mitosis. Dysregulation of AURKB, often characterized by its overexpression, has been implicated in various malignancies, including breast cancer. However, the mechanisms governing its dysregulation remain incompletely understood. Here, we identify a pivotal role for the MOF/MSL complex—which includes the histone acetyltransferase MOF (KAT8)—in modulating AURKB stability through acetylation at lysine 215 (K215). This post-translational modification inhibits AURKB ubiquitination, thereby stabilizing its protein levels. MOF/MSL-mediated AURKB stabilization promotes the proper assembly of the chromosomal passenger complex (CPC), ensuring mitotic fidelity. Notably, inhibition of MOF reduces AURKB K215 acetylation, leading to decreased AURKB expression and activity. Consequently, this downregulation suppresses expression of the downstream oncogene c-MYC, ultimately attenuating the malignant proliferation of breast cancer cells. Collectively, our findings reveal a novel mechanism by which lysine acetylation regulates AURKB stability, highlight the significance of the MOF-AURKB-c-MYC axis in breast cancer progression, and suggest potential therapeutic strategies targeting this pathway in clinical settings. Full article

WEE1 kinase is a crucial cell cycle regulatory protein that controls the timing of mitotic entry. WEE1, via inhibition of Cyclin-dependent Kinase 1 (CDK1) and Cyclin-dependent Kinase 2 (CDK2), governs the G2-M checkpoint by inhibiting entry into mitosis. The state of balance between WEE family kinases and CDC25C phosphatases restricts CDK1/CycB activity. The WEE kinase family consists of WEE1, PKMYT1, and WEE2 (WEE1B). WEE1 and PKMYT1 regulate entry into mitosis during cell cycle progression, whereas WEE2 governs cell cycle progression during meiosis. Recent studies have identified WEE1 as a potential therapeutic target in several cancers, including therapy-resistant triple-negative breast cancer. Adavosertib’s clinical promise was challenged by inter-individual variations in response and side effects. Because of these promising preclinical outcomes, other WEE1 kinase inhibitors (Azenosertib, SC0191, IMP7068, PD0407824, PD0166285, WEE1-IN-5, Zedoresertib, WEE1-IN-8, and ATRN-1051) are being developed, with several currently being evaluated in clinical trials or as an adjuvant to chemotherapies. Preclinical studies show WEE1 inhibitors induce MHC class 1 antigens and STING when given as combination therapies, suggesting potential additional therapeutic opportunities. Reliable predictors of clinical responses based on mechanistic insights remain an important unmet need. Herein, we review the role of WEE1 inhibition therapy in breast cancer. Full article

Human papillomavirus (HPV) 16 is transported in a retrograde fashion from the cell surface to the Golgi apparatus. Prior to mitosis, the virus loses association with the Golgi and, following nuclear envelope breakdown, is found associated with the condensed mitotic chromatin. The intervening steps have not been well defined. It was previously demonstrated that the virus is transported to the mitotic chromosomes in vesicles. Here, we describe the role of the endoplasmic reticulum (ER) in the post-Golgi trafficking and the importance of the ER-generated coat protein complex II (COPII) anterograde trafficking pathway in HPV infection. HPV pseudovirus (PsV) colocalized with COPII components and silencing of this pathway inhibited HPV infection. Additionally, the inner COPII coat protein, Sec24b, could be biochemically isolated in association with HPV capsid proteins. This study provides insight into the mechanism of post-Golgi HPV trafficking. Full article

Despite decades of research, cancer continues to be a disease of great concern to millions of people around the world. It has been responsible for a total of 609,820 deaths in the U.S. alone in 2023. Over the years, many drugs have been developed to remove or reduce the disease’s impact, all with varying mechanisms of action and side effects. One class of these drugs is small-molecule mitotic inhibitors. These drugs inhibit cancer cell mitosis or self-replication, impeding cell proliferation and eventually leading to cell death. In this paper, small-molecule mitotic inhibitors are discussed and classified through their discovery, underlying chemistry, and mechanism(s) of action. The binding/inhibition of microtubule-related proteins, DNA damage through the inhibition of Checkpoint Kinase 1 protein, and the inhibition of mitotic kinase proteins are discussed in terms of their anticancer activity to provide an overview of a variety of mitotic inhibitors currently commercially available or under investigation, including those in ongoing clinical trial. Clinical trials for anti-mitotic agents are discussed to track research progress, gauge current understanding, and identify possible future prospects. Additionally, antibody–drug conjugates that use mitotic inhibitors as cytotoxic payloads are discussed as possible ways of administering effective anticancer treatments with minimal toxicity. Full article

The Ras/PI3K/ERK signaling network is frequently mutated and overactivated in various human cancers. Focal adhesion kinase (FAK) is commonly overexpressed in several cancer types and has been implicated in treatment resistance mechanisms. A positive feedback loop between Ras, PI3K, the cytoskeleton, and FAK was previously shown to drive Ras signaling excitability. In this study, we investigated the effectiveness of targeting Ras signaling excitability by concurrently inhibiting FAK and PI3K in cervical and pancreatic cancer cells, which depend on activation Ras/PI3K signaling. We found that the combination of FAK and PI3K inhibitors synergistically suppressed the growth of cervical and pancreatic cancer cell lines through increased apoptosis and decreased mitosis. PI3K inhibitors alone caused only a transient suppression of downstream AKT activity and paradoxically increased FAK signaling in cancer cells. The addition of an FAK inhibitor effectively counteracted this PI3K-inhibitor-induced FAK activation. Furthermore, PI3K inhibitors were found to activate multiple receptor tyrosine kinases (RTKs), including insulin receptor, IGF-1R, EGFR, HER2, HER3, AXL, and EphA2. Taken together, our results suggest that FAK inhibition is necessary to counteract the compensatory RTK activation induced by PI3K inhibitors, thereby achieving more effective suppression of cancer cell growth. These findings highlight the therapeutic potential of combined FAK and PI3K inhibition in cancer treatment. Full article

Plasma membrane plays a pivotal role in orchestrating motility and invasive processes, as well as mitosis and genome expression. Indeed, specialized regions of the plasma membrane enriched in phosphoinositides—namely PIP2 and PIP3—can accommodate the requirements of the dynamic interface, which mediates the interplay between cells and their microenvironment. The fine-tuned balance between the two phosphoinositides is instrumental in regulating cytoskeleton organization, motility, ion channel activation, and membrane traffic. The balanced expression of PIP2/PIP3 fulfills these functions by activating pathways through several transporter and receptor proteins. These dynamic interactions modulate the interplay with the extracellular environment by decreasing/increasing their exposure on the cell surface. In this way, lipid structures can rapidly either dismiss or recruit specific proteins, eventually favoring their cooperation with membrane receptors and ion channels. Particularly, exposure of proteins can be managed through the internalization of plasma membrane segments, while receptor signaling can be desensitized by their removal from the cell surface. Notably, the equilibrium between PIP2 and PIP3 is largely dependent on inositol availability, as inositol addition enhances PIP2 content while reducing PIP3 via PI3K inhibition. Pharmacological modulation of PIP2/PIP3 balance promises to be an interesting target in different clinical settings. Full article

New therapeutic approaches that antagonize tumour-promoting phenotypes in lung cancer are needed to improve patient outcomes. Chromosomal instability (CIN) is a hallmark of lung cancer characterized by the ongoing acquisition of genetic alterations that include the gain and loss of whole chromosomes or segments of chromosomes as well as chromosomal rearrangements during cell division. Although it provides genetic diversity that fuels tumour evolution and enables the acquisition of aggressive phenotypes like immune evasion, metastasis, and drug resistance, too much CIN can be lethal because it creates genetic imbalances that disrupt essential genes and induce severe proteotoxic and metabolic stress. As such, sustaining advantageous levels of CIN that are compatible with survival is a fine balance in cancer cells, and potentiating CIN to levels that exceed a tolerable threshold is a promising treatment strategy for inherently unstable tumours like lung cancer. Kinesins are a superfamily of motor proteins with many members having functions in mitosis that are critical for the correct segregation of chromosomes and, consequently, maintaining genomic integrity. Accordingly, inhibition of such kinesins has been shown to exacerbate CIN. Therefore, inhibiting mitotic kinesins represents a promising strategy for amplifying CIN to lethal levels in vulnerable cancer cells. In this review, we describe the concept of CIN as a therapeutic vulnerability and comprehensively summarize studies reporting the clinical and functional relevance of kinesins in lung cancer, with the goal of outlining how kinesin inhibition, or “targeting kinesins”, holds great potential as an effective strategy for treating lung cancer. Full article

The regeneration of endothelial cells (ECs) lining arteries, veins, and large lymphatic vessels plays an important role in vascular pathology. To understand the mechanisms of atherogenesis, it is important to determine what happens during endothelial regeneration. A comparison of these processes in the above-mentioned vessels reveals both similarities and some significant differences. Regeneration is carried out by moving intact ECs from the edges of the viable endothelial layer towards the centre of the EC damage zone. A sharp decrease in contact inhibition leads to the spreading of the edges of the ECs situated on the damage border. This stimulates the second row of ECs to enter the S-phase, then the G2 phase of cell cycle, and finally mitosis. In all three types of vessels studied, mitotically dividing ECs were found using correlation light and electron microscopy. These ECs have a body protruding into the lumen of the vessel, covered with micro-villi and other outgrowths. The level of EC rounding and protruding is highest in the arteries and least pronounced in the lymphatic vessels. The intercellular contacts of mitotically dividing cells become wider. The EC division leads to an increase in the density of ECs. ECs moving over the damaged area and partially outside the damaged area acquire a fusiform shape. In the process of regeneration of arterial endothelium, the damaged ECs are removed. Then health ECs move to a surface devoid of endothelium, and detach spreading out, flattened platelets from the luminal surface of the vessel. In the veins, ECs grow on the surface of platelets and microthrombi. In lymphatic vessels, ECs detach from the basement membrane slower than in the veins and arteries. There, the migrating ECs grow under fibrin fibres. After some time (usually after 30 days), the EC mosaic returns to normal in all three types of vessels. Full article

This review evaluates the cytotoxic potential of the Sesbania genus, with a focus on Sesbania sesban, Sesbania grandiflora, and Sesbania cannabina. These species, known for their diverse phytochemical compositions, exhibit notable cytotoxic effects that suggest their utility in natural cancer treatments. Compounds such as quercetin, kaempferol, and sesbagrandiforian A and B have been highlighted for their strong antioxidant and antiproliferative effects, further emphasizing their therapeutic potential. The genus Sesbania exhibits a wide range of in vitro and in vivo bioactivities. Extensive research on S. grandiflora has uncovered mechanisms such as the activation of caspase cascades and the induction of apoptosis, attributed to its rich content of flavonoids and alkaloids. Notably, sesbanimides derived from S. grandiflora seeds have demonstrated potent cytotoxic effects by disrupting mitochondrial function. While S. sesban and S. cannabina have been less extensively studied, early findings highlight their potential through the inhibition of key cancer pathways and the identification of bioactive compounds such as galactomannan derivatives and 2-arylbenzofurans. Notably, the galactomannan derivatives from S. sesban exhibit significant immune-modulating properties. Additionally, nanoparticles synthesized from Sesbania species, including Cadmium oxide and PEGylated silver nanoparticles, have demonstrated promising cytotoxic activity by disrupting mitosis and enhancing immune responses. While further research is warranted, the Sesbania genus offers a promising basis for the development of innovative anticancer therapies. Full article

Mucinous epithelial ovarian cancer (mEOC) is a rare subtype of epithelial ovarian cancer, characterized by poor responses to standard platinum-based chemotherapy. Polo-like kinase 1 (PLK1) is a key regulator of mitosis and cell cycle progression and its inhibition has been recently identified as a target in mEOC. In this study, we aimed to identify further therapeutic targets in mEOC using a CRISPR/Cas9 library targeting 3015 genes, with and without treatment with onvansertib, a PLK1 inhibitor. We identified twelve genes associated with cell survival (ZC2HC1C, RPA2, KIN17, TUBG1, SMC2, CDC26, CDC42, HOXA9, TAF10, SENP1, MRPS31, and COPS2) and three genes (JUND, CARD9, and BCL2L2) in synthetic lethality with onvansertib treatment. We validated that SENP1 downregulation is important for the growth of mEOC cells through esiRNA interference and the use of a pharmacological inhibitor Momordin Ic. The downregulation of CARD9 and BCL2L2 combined with subtoxic doses of onvansertib interfered with mEOC cell growth. Interestingly, the combination of navitoclax, an inhibitor of BcL2 family members including BCL2L2, was synergistic in all four of the mEOC cell lines tested and substantially induced cell death through apoptosis. These data support the use of a combination of navitoclax and onvansertib as a new therapeutic strategy for mEOC. Full article