Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus (Probable). Phosphorylates MAP2K1, and thereby activates the MAP kinase signal transduction pathway (PubMed:21441910, PubMed:29433126). Phosphorylates PFKFB2 (PubMed:36402789). May play a role in the postsynaptic responses of hippocampal neurons (PubMed:1508179)

Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer.

Abstract: BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all patients with colorectal cancer (CRC), and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as encorafenib are ineffective due to MAPK pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, although approved therapies, results in short survival benefits and frequent treatment resistance and relapse1-3. Here, through rational chemical library design coupled with parallel proteomic screening, we identified dHuR as a molecular glue degrader of human antigen R (HuR), an RNA-binding protein that drives tumour growth, invasion and therapy resistance. dHuR binds to the CRBN ubiquitin ligase to create a unique benzofuran-tethered composite surface to recruit HuR as a neosubstrate by engaging its β-hairpin G-loop degron, as revealed by the cryo-electron microscopy structure of the ternary complex. dHuR abrogated BRAF expression by inducing its exon 18 skipping, and demonstrated superior suppression of BRAF-mutant CRC tumours including those gaining resistance to BRAF inhibitors. Finally, we performed kinome library CRISPR screening and revealed that inactivation of EGFR or MEK enhanced dHuR cytotoxicity, thus establishing a combinatorial strategy to treat patients with refractory BRAF-mutant CRC.

Pharmacologic reprogramming of virus-tumor crosstalk enhances measles virus antitumor activity in BRAF mutant colorectal cancer models.

Journal of experimental & clinical cancer research : CR

Abstract: Oncolytic viruses are promising cancer biotherapies but often show limited durability as single agents due to tumor-intrinsic resistance mechanisms. Because therapeutic efficacy is shaped by dynamic virus-tumor-stromal interactions, pharmacologic strategies that reprogram this interface may enhance virotherapy responses. Here, we investigate whether targeting tumor stress and survival pathways with triptolide and its prodrug Minnelide can enhance the oncolytic efficacy of measles virus in colorectal cancer. The in vitro effects of CD46 targeted (MV-GFP) and dual targeted (MV-CD46-muPA) oncolytic MV, alone and with Triptolide were assessed in human CRC cell lines. Mechanistic studies included gene expression analysis, functional proteomics, and western blotting. In vivo efficacy of MV-CD46-muPA combined with Minnelide was evaluated in HT29 and HCT116 xenografts. Biological effects were further characterized using transcriptomic profiling (RNA-seq), targeted gene expression (NanoString), and histological analysis. Triptolide enhanced MV mediated oncolysis in vitro, particularly in BRAF V600E mutant CRC cell lines, and modulated key cancer pathways including AKT, apoptosis and metabolism. In vivo, Minnelide significantly improved the efficacy of systemically administered MV-CD46-muPA in human CRC xenografts, with greater effects in BRAF mutant (HT29) models. The combination modulated cell cycle, metabolism, and survival associated genes, promoted apoptosis, and improved intratumoral viral distribution. These molecular effects resulted in reduced tumor cell proliferation (Ki67), decreased angiogenesis (CD31), and increased apoptosis (TUNEL) relative to single agents. Triptolide and Minnelide significantly enhance the oncolytic efficacy of measles virus in colorectal cancer, particularly in BRAF-mutant tumors in vivo, through reprogramming of virus-tumor-stromal interactions. This reprogramming arises from coordinated modulation of survival, metabolic, and stromal signaling pathways and is accompanied by improved intratumoral viral distribution. These findings position virus-tumor-stromal crosstalk as a central mechanistic axis of virotherapy response and provide a strong rationale for the translational and clinical development of rational virus-drug combination strategies in colorectal cancer and other malignancies.

TIL cell therapy in HIV positive patient with metastatic melanoma: case report.

Abstract: Tumor-infiltrating lymphocyte (TIL) therapy is an emerging treatment for patients with metastatic melanoma whose disease has progressed on immune checkpoint inhibitors. However, individuals living with well-controlled human immunodeficiency virus (HIV) have historically been excluded from clinical trials evaluating adoptive cell therapies, leaving uncertainty regarding safety, tolerability, immune effects, and oncologic response in this population. We present the first known case of a patient with virologically suppressed HIV receiving TIL therapy for immunotherapy-refractory metastatic melanoma. A 37-year-old man with long-standing HIV on antiretroviral therapy (ART) developed rapidly progressive, BRAF-V600E mutant metastatic melanoma involving bulky axillary disease and pulmonary metastases despite anti-PD-1 therapy, combined checkpoint blockade, and BRAF/MEK-targeted therapy. His course prior to TIL therapy was notable for minimal treatment-related toxicities and intermittent detectable low-level HIV viremia. After multidisciplinary review, he underwent TIL harvest followed by lymphodepleting chemotherapy, lifileucel infusion, and high-dose interleukin-2 (IL-2). TIL therapy was tolerated with expected toxicities, including grade 1 cytokine release syndrome and IL-2-associated grade 3 hypotension requiring brief vasopressor support. At day 44, imaging demonstrated a partial response with decreased pulmonary metastases and stabilization of axillary disease. Progression of disease was observed by day 86. CD4 counts fluctuated markedly throughout treatment, though virologic suppression was ultimately restored by day 100. This case demonstrates that TIL therapy can be feasibly administered to a patient with well-controlled HIV, with manageable toxicity and early radiographic response. These findings underscore the need for prospective inclusion of people living with HIV in cellular therapy trials to better characterize safety, immune dynamics, and predictors of durable benefit.

δ-Tocotrienol re-sensitizes vemurafenib-resistant melanoma cells to BRAF inhibition via modulation of AKT signaling.

Food research international (Ottawa, Ont.)

Abstract: Melanoma is a highly aggressive skin cancer, with mortality largely driven by the development of resistance to BRAF-targeted therapies such as vemurafenib. Although several combination strategies have been explored, durable responses in resistant disease remain limited, highlighting the need for new therapeutic approaches. δ-tocotrienol (δ-TT), a member of the vitamin E family, has shown anticancer activity in different tumor models, but its effects in BRAF inhibitor-resistant melanoma remain poorly characterized, particularly in the context of acquired resistance and combination treatment strategies. In this study, we investigated the antitumor activity of δ-TT and its ability to restore sensitivity to vemurafenib in resistant melanoma models. To this end, two human melanoma cell lines with acquired resistance (A375R and SK-MEL-28R) were treated with δ-TT alone or in combination with vemurafenib. δ-TT significantly reduced cell viability and clonogenic potential, inducing G1/S cell cycle arrest via downregulation of cyclin D1/D3 and upregulation of p21. It also triggered mitochondrial apoptosis, as indicated by loss of mitochondrial membrane potential, increased Bax/Bcl-2 ratio, cytochrome c release, and activation of caspase-3 and PARP cleavage. In addition, δ-TT impaired migration and invasion by decreasing MMP-2 expression and secretion. These effects were associated with inhibition of AKT signaling. Notably, δ-TT restored responsiveness to vemurafenib, indicating a synergistic interaction in resistant melanoma cells. Overall, these findings provide mechanistic evidence supporting a potential role for δ-TT as a modulator of drug response and support further investigation of δ-TT-based combination strategies to overcome therapeutic resistance in melanoma.

Implications of ADP-Ribosylation Factor-Like Protein 4C (ARL4C) in Human Neoplasia With Special Emphasis on Ameloblastoma: A Scoping Review.

Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology

Abstract: ADP-ribosylation factor-like protein 4C (ARL4C), a member of the ARF small GTP-binding protein subfamily, has emerged from its role as an epithelial growth regulator to become a central molecule in cancer biology. This scoping review was conducted according to the PRISMA-ScR framework, systematically maps literature from PubMed, Scopus and Web of Science up to December 2024 to synthesise evidence on ARL4C's regulatory mechanisms and its implications in tumourigenesis and relevance to ameloblastoma. Originally recognised for its role in tissue morphogenesis, ARL4C is now known to drive cancer cell proliferation, migration and invasion when dysregulated. Its expression is modulated by major signalling cascades including Wnt/MAPK, PI3K/AKT and TGF-β, as well as epigenetic factors. While primarily acting as an oncogenic driver, ARL4C exhibits context-dependent roles, occasionally functioning as a tumour suppressor. In ameloblastoma, a locally aggressive odontogenic tumour, ARL4C expression correlates with invasion and bone resorption. Notably, this influence appears independent of BRAF mutation status, suggesting a unique pathological role in this setting. ARL4C stands at the intersection of fundamental cell biology and clinical oncology. It holds promise as a biomarker for prognosis and recurrence and as a potential therapeutic target. However, its dual nature highlights the complexity of cancer signalling networks. Future research involving larger patient cohorts is essential to validate ARL4C's utility in precision oncology, particularly for the management of ameloblastoma.


Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN

Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins (PubMed:9187108, PubMed:9256433, PubMed:9616126). Also functions as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring of PtdIns(3,4,5)P3/phosphatidylinositol 3,4,5-trisphosphate, PtdIns(3,4)P2/phosphatidylinositol 3,4-diphosphate and PtdIns3P/phosphatidylinositol 3-phosphate with a preference for PtdIns(3,4,5)P3 (PubMed:16824732, PubMed:26504226, PubMed:9593664, PubMed:9811831). Furthermore, this enzyme can also act as a cytosolic inositol 3-phosphatase acting on Ins(1,3,4,5,6)P5/inositol 1,3,4,5,6 pentakisphosphate and possibly Ins(1,3,4,5)P4/1D-myo-inositol 1,3,4,5-tetrakisphosphate (PubMed:11418101, PubMed:15979280). Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival (PubMed:31492966, PubMed:37279284). The unphosphorylated form cooperates with MAGI2 to suppress AKT1 activation (PubMed:11707428). In motile cells, suppresses the formation of lateral pseudopods and thereby promotes cell polarization and directed movement (PubMed:22279049). Dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion formation (PubMed:22279049). Required for growth factor-induced epithelial cell migration; growth factor stimulation induces PTEN phosphorylation which changes its binding preference from the p85 regulatory subunit of the PI3K kinase complex to DLC1 and results in translocation of the PTEN-DLC1 complex to the posterior of migrating cells to promote RHOA activation (PubMed:26166433). Meanwhile, TNS3 switches binding preference from DLC1 to p85 and the TNS3-p85 complex translocates to the leading edge of migrating cells to activate RAC1 activation (PubMed:26166433). Plays a role as a key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Involved in the regulation of synaptic function in excitatory hippocampal synapses. Recruited to the postsynaptic membrane upon NMDA receptor activation, is required for the modulation of synaptic activity during plasticity. Enhancement of lipid phosphatase activity is able to drive depression of AMPA receptor-mediated synaptic responses, activity required for NMDA receptor-dependent long-term depression (LTD) (By similarity). May be a negative regulator of insulin signaling and glucose metabolism in adipose tissue. The nuclear monoubiquitinated form possesses greater apoptotic potential, whereas the cytoplasmic nonubiquitinated form induces less tumor suppressive ability (PubMed:10468583, PubMed:18716620) Functional kinase, like isoform 1 it antagonizes the PI3K-AKT/PKB signaling pathway. Plays a role in mitochondrial energetic metabolism by promoting COX activity and ATP production, via collaboration with isoform 1 in increasing protein levels of PINK1

Engineered targeted enhancement of translation in mammalian cell.

Abstract: While the central dogma outlines DNA-to-protein information flow, existing gene regulators mainly target transcription. Here, we developed the λN-Guided RNA Targeting System (λGRTS), a CRISPR-independent platform enhancing mammalian mRNA translation via specific translation-guiding RNAs (tgRNAs). λGRTS integrates λN (high-affinity BoxB binder), mutated eIF4E1 (ablated non-specific 5' cap binding, retains TIC recruitment), and auxiliary factors (HuR for dsRNA stabilization, PABP and RRM2-RRM3 for mRNA closed loops). Optimized 22-nt tgRNAs (targeting 58 bp upstream of mRNA ATG in 5' UTR) and NES-tagged proteins maximized efficacy. λGRTS outperformed dCasRX (smaller ~ 50 kDa vs. ~ 150 kDa, single tgRNA vs. crRNA-tracrRNA), boosting functional proteins (e.g., GFP). It activated P53/PTEN, suppressing GBM cell proliferation, inducing G1 arrest, and reducing invasion in vitro. In vivo, lentiviral λGRTS inhibited orthotopic GBM in nude mice, extended survival by approximately 35-40 days, with IHC confirming P53/PTEN upregulation. Mass spectrometry showed no off-target effects. Cross-species tests (human, mouse, bovine cells) validated broad applicability via conserved eIF4E1. λGRTS offers a specific, safe translation-centric tool for gene regulation and oncology research.

Generation of a stable mouse endometrial tumor-derived cell line using conditional reprogramming.

Abstract: Endometrial cancer (EC) is a common malignancy of the female reproductive tract worldwide. While comprehensive genomic analyses have identified multiple genetic alterations in EC, disease models remain relatively rare, limiting the ability to conduct disease studies. Establishing a hybrid in vitro and in vivo model of EC and comparing it to its in vivo counterpart could greatly advance research into EC mechanisms and treatment strategies. We established genetically engineered EC mice (Pten flox/+; Stk11 flox/flox; LTF-Cre (PSC)) and constructed a corresponding epithelial cell line from isolated uterine tumor tissues using conditional reprogramming techniques. The cell line was successfully passaged, frozen, and stored in a biobank, providing a valuable resource for future EC research. The PSC-derived cell line stably retained the mutant alleles of Pten and Stk11 during passaging, preserving the genetic profile of the original tumor. In addition, we performed various functional assays on isolated mouse cell linesand formed tumors after subcutaneous implantation of cells in immunodeficient mice and C57BL/6 mice with an intact immune system. Hematoxylin and eosin (H&E) staining and immunohistochemical staining were used to characterize the histopathology and biomarkers of the subcutaneously implanted tumors, which were highly similar to those of the parental mouse uterine tumors. The isolated mouse cell line provides a powerful platform for basic and translational EC studies, matching well with the corresponding in vivo models. The fidelity of the cell line to human-relevant genetic alterations and tumor biology makes it a valuable tool for investigating EC pathogenesis and evaluating novel therapeutic approaches.

The WYZ-1 mouse glioblastoma stem cell model: A novel preclinical tool for tumor and therapy studies.

Abstract: We established a novel syngeneic glioblastoma stem cell (GSC) line from PDGFB-driven RCAS/tv-a glioblastomas and subsequently generated a Pten-deficient derivative, WYZ-1. In vitro, WYZ-1 cells exhibited robust self-renewal, high expression of GSC markers (CD133, Nestin, SOX2), and multipotent differentiation into neuronal and astrocytic lineages. In vivo, intracranial implantation in immunocompetent mice produced highly infiltrative and vascularized tumors with marked proliferation, necrosis, and white matter invasion, closely recapitulating key histopathological features of human glioblastoma. Immunohistochemical analysis confirmed the retention of oncogenic, stem-like, and mesenchymal-associated markers. Importantly, WYZ-1 tumors displayed an immune-excluded ("cold") tumor microenvironment characterized by dense infiltration of immunosuppressive macrophages/microglial cells within the tumor core and restricted localization of exhausted T cells to the tumor margins. Consistent with these features, WYZ-1 tumors are resistant to temozolomide and anti-PD-1 monotherapy, with only a modest survival benefit observed following CTLA-4 blockade. Collectively, these findings establish WYZ-1 as a highly aggressive, stem-like, and immunocompetent glioblastoma model that mirrors the therapeutic resistance of human disease and provides a valuable platform for investigating tumor biology and evaluating novel immunotherapeutic strategies.

Oncogenic impact of PIK3CA, KRAS, and PTEN mutations in cervical cancer among South Indian women.

Advances in clinical and experimental medicine : official organ Wroclaw Medical University

Abstract: Cervical cancer (CC) affects millions of women worldwide. This condition is strongly associated with human papillomavirus (HPV) infection. Oncogenic alterations are known to contribute to the development and progression of CC. This study aimed to screen for variations in selected genes associated with CC, including PIK3CA, KRAS, and PTEN, and to detect high-risk HPV genotypes 16, 18, 31, 45, 52, and 58 using gene-specific polymerase chain reaction (PCR), followed by single-strand conformation polymorphism (SSCP) analysis and confirmation using bidirectional DNA sequencing. The study included 414 participants, comprising 204 cases and 210 controls. Healthy controls were disease-free individuals participating in regular health checkups. Selected gene mutations were analyzed using PCR-based assays, SSCP, and sequence analysis. HPV genotyping was also performed. All study participants were analyzed for mutations in the PIK3CA, KRAS, and PTEN genes. The analysis revealed mutation frequencies of 6.37% for KRAS, 2.45% for PTEN, and 16.66% for PIK3CA in CC cases. These findings suggest that PIK3CA and KRAS mutations are more frequent in patients with CC than PTEN mutations. HPV infection was detected in 87.10% of patients with CC, 79.24% of participants with high-grade squamous intraepithelial lesions (HSIL), and 60.34% of participants with low-grade squamous intraepithelial lesions (LSIL). This study contributes to understanding the genetic basis of CC in South India and may facilitate the development of future targeted therapies. The high prevalence of HPV underscores its etiological significance in CC. These findings contribute to a deeper understanding of the molecular mechanisms underlying CC in this population and may support the development of targeted therapeutic strategies for high-risk individuals. Future prospective studies and functional analyses are warranted to validate the clinical significance of these mutations and clarify their role in disease progression.

SARS-CoV-2 ORF3a suppresses host antiviral interferon responses by promoting STUB1-mediated PTEN proteasomal degradation.

Abstract: Human coronaviruses (HCoVs) are a group of RNA viruses characterized by high genetic variability and cross-species transmission potential. They can cause a wide spectrum of respiratory illnesses, ranging from mild upper respiratory tract infections to severe pneumonia, and acute respiratory distress syndrome. PTEN, a well-known tumor suppressor, not only plays a crucial role in tumorigenesis but also enhances antiviral immunity by regulating IRF3 phosphorylation and promoting type I interferon production. In this study, we observed that PTEN significantly inhibited the replication of various HCoVs, including SARS-CoV-2, HCoV-229E, and HCoV-OC43. However, SARS-CoV-2 infection antagonizes the antiviral function of PTEN. Mechanistically, PTEN undergoes ubiquitination at lysine 6, followed by proteasomal degradation after SARS-CoV-2 infection. Through screening, it was found that STUB1 is the key E3 ligase responsible for PTEN degradation under SARS-CoV-2 infection. Furthermore, screening of SARS-CoV-2-encoded proteins revealed that ORF3a promotes STUB1-mediated PTEN ubiquitination and degradation at K6. Previous studies have shown that Oroxin B can exert the effect of a PTEN agonist by upregulating the expression of PTEN. In this study, we demonstrated that Oroxin B significantly enhances antiviral responses in mice. In conclusion, this study reveals the molecular mechanism by which SARS-CoV-2 evades PTEN-mediated antiviral effects, providing new insights for the development of PTEN-targeted antiviral strategies. Human coronaviruses continue to threaten global health, yet how these viruses evade our natural antiviral defenses remains poorly understood. This study reveals that PTEN, a well-known tumor suppressor, also acts as a powerful antiviral molecule capable of limiting multiple human coronaviruses, including SARS-CoV-2. We further show that SARS-CoV-2 dismantles this protection by triggering PTEN degradation through the host enzyme STUB1 and the viral protein ORF3a. This discovery uncovers a previously unknown strategy used by coronaviruses to weaken innate immunity. Importantly, we identify Oroxin B as a promising compound that enhances antiviral responses in vivo. Together, our findings provide new insight into how coronaviruses disarm host defenses and highlight PTEN as a potential target for broad-spectrum antiviral therapies.