Biochemistry and Biophysics Reports最新文献

{"title":"Fibroblasts fluctuating between mesenchyme and epithelium are involved in hair follicle mesenchyme development","authors":"Yoshikazu Hirose ,&nbsp;Asaka Miura ,&nbsp;Yuya Ouchi ,&nbsp;Tomomi Kitayama ,&nbsp;Souki Omura ,&nbsp;Takashi Shimbo ,&nbsp;Akio Tanaka ,&nbsp;Manabu Fujimoto ,&nbsp;Kotaro Saga ,&nbsp;Katsuto Tamai","doi":"10.1016/j.bbrep.2025.102006","DOIUrl":"10.1016/j.bbrep.2025.102006","url":null,"abstract":"<div><div>The transition between the mesenchyme and epithelium contributes to the development of various tissues. During skin development, epithelial-mesenchymal transition in the ectodermal epithelia is involved in the development of the dermal mesenchyme in early embryos. However, the precise roles and functions of epithelial-mesenchymal/mesenchymal-epithelial transition in cutaneous development have not been fully elucidated. In this study, we aimed to elucidate these roles and functions in the neonatal mouse skin. We conducted single-cell RNA sequencing and immunohistochemical analyses to search for <em>Pdgfra</em>-expressing (<em>Pα</em>⁺) fibroblasts with transition activities to/from <em>Krt5</em>-expressing keratinocytes. We determined that the <em>Pα</em>⁺/<em>Krt5</em>-lineage (<em>K5</em>^lin+) fibroblasts significantly contributed to developing hair follicle dermal stem cells to generate lower dermal papilla cells and lower dermal sheath cells. In the developing mouse skin, <em>K5</em>^lin⁺ fibroblasts appeared concurrently with hair follicle development and formed outer edge cells in the early dermal papilla on embryonic day 16.5. <em>K5</em>^lin⁺ hair follicle mesenchymal cells were also maintained in aged mouse skin. These results provide insights into the role and function of the transition between the mesenchyme and epithelium in hair follicle development and maintenance.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102006"},"PeriodicalIF":2.3,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143823955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of an anti-CD3 VHH and construction of an anti-CD3/anti-EGFR bispecific tandem VHH as a cancer cell targeting drug construct","authors":"Takuya Asanuma ,&nbsp;Peiwei Ding ,&nbsp;Yuki Kato ,&nbsp;Takeshi Nakanishi ,&nbsp;Ryutaro Asano ,&nbsp;Koki Makabe","doi":"10.1016/j.bbrep.2025.102015","DOIUrl":"10.1016/j.bbrep.2025.102015","url":null,"abstract":"<div><div>Recently, the development of T-cell engager cancer therapeutics, consisting of anticancer and anti-T-cell antibody parts to engage the T-cell to the cancer site, has gained interest. Anti-CD3 antibodies are predominantly used to achieve specific binding to T-cells for the T-cell engager construction. Various kinds of anti-CD3 IgG clones have been developed and engineered, but the available anti-CD3 VHH, a single variable domain of a dromedary heavy-chain antibody, clones are limited in number. Thus, the assessment of the available anti-CD3 VHHs is important for therapeutic applications. Here, we demonstrated the expression and characterization of an anti-CD3 VHH clone, 117G03, and evaluated this T-cell engager with an anti-EFGR VHH in a bispecific format to assess the developability of this anti-CD3 VHH clone. 117G03 was expressed as a monomer in the soluble fraction and demonstrated decent thermal stability with binding activity against a CD3-positive cell line. The T-cell engager construct was prepared using the refolding method and exhibited enhanced cytotoxic activity against the epidermal growth factor receptor (EGFR)-positive cell line mediated by activated T-cells. These results indicate that 117G03 can be utilized for T-cell engager applications.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102015"},"PeriodicalIF":2.3,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and evaluation of isoquinolinyl and pyridinyl-based dual inhibitors of fatty acid amide hydrolase and soluble epoxide hydrolase to alleviate orofacial hyperalgesia in the rat","authors":"Daniel Carr ,&nbsp;Siena Gunari ,&nbsp;Gabrielle Gorostiza ,&nbsp;Madison Mercado ,&nbsp;Lucy Pavana ,&nbsp;Leah Duong ,&nbsp;Karen Gomez ,&nbsp;Steve Salinas ,&nbsp;Coral Garcia ,&nbsp;Amanda Tsang ,&nbsp;Christophe Morisseau ,&nbsp;Bruce D. Hammock ,&nbsp;Stevan Pecic ,&nbsp;Ram Kandasamy","doi":"10.1016/j.bbrep.2025.102009","DOIUrl":"10.1016/j.bbrep.2025.102009","url":null,"abstract":"<div><div>The treatment of orofacial pain disorders is poor. Both opioids and serotonin agonists are commonly used; however, they produce dangerous and unpleasant side effects. Therefore, there is an urgent need to identify new pharmacological treatments that can resolve orofacial pain. Moreover, a treatment that engages multiple mechanisms using one compound may be advantageous. Fatty acid amide hydrolase (FAAH) and soluble epoxide hydrolase (sEH) are two enzymes that can regulate both pain and inflammation via independent pathways. Small molecules that inhibit both enzymes simultaneously were previously synthesized and produced antinociception <em>in vivo</em>. Quinolinyl-based dual inhibitors of FAAH and sEH can inhibit acute inflammatory pain in rats. Here, following on these findings, we generated 7 new isoquinolinyl- and 7 pyridinyl-based analogs and tested their inhibition at both enzymes. Structure-activity relationship study coupled with docking experiments, revealed that the isoquinoline moiety is well-tolerated in the binding pockets of both enzymes, yielding several analogs with nanomolar activity in enzymatic assays. All newly synthesized analogs were assessed in the solubility assay at pH 7.4, and we determined that isoquinolinyl- and substituted pyridinyl-analogs exhibit limited solubility under the experimental conditions. The most potent inhibitor, <strong>4f</strong>, with IC₅₀ values in the low nanomolar range for both enzymes, was evaluated in a plasma stability assay in human and rat plasma where it showed a moderate stability. Primary binding assays revealed that <strong>4f</strong> does not engage any opioid or serotonin receptors. A high dose (3 mg/kg) of <strong>4f</strong> reversed orofacial hyperalgesia following pretreatment with nitroglycerin and orofacial injection of formalin; however, this same dose did not inhibit acute orofacial inflammatory pain or restore pain-depressed wheel running. These findings indicate that simultaneous inhibition of FAAH and sEH using isoquinolinyl-based dual inhibitors may only reverse certain components of orofacial hyperalgesia.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102009"},"PeriodicalIF":2.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143807549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intrinsic Alu affects for RNA splicing in a minigene model","authors":"Mina Nakama ,&nbsp;Bunta Imanaka ,&nbsp;Yuma Kimoto","doi":"10.1016/j.bbrep.2025.102002","DOIUrl":"10.1016/j.bbrep.2025.102002","url":null,"abstract":"<div><div><em>Alu</em> elements are commonly located in the introns of primate genomes and, once transcribed, can alter splicing patterns. The insertion of an antisense <em>Alu</em> element into intron 9 was shown to enhance exon 10 skipping in a previously developed <em>ACAT1</em> minigene model including exon 9–exon 11. This study investigates two intrinsic original <em>Alu</em>s' role located in the intron in <em>ACAT1</em> sequence using the same minigene splicing system. The deletion of intrinsic full <em>Alu</em>Sx originally located in intron 10 resulted in intron 10 retention, whereas the partial <em>Alu</em>Jb or antisense <em>Alu</em>Sx in the same intron was not sufficient for this process. Even normal splicing transcript wasn't shown without intrinsic full <em>Alu</em>Sx. Exon skipping was induced under the condition in which the intronic splice out prior to. Also, exon skipping was required with two close <em>Alu</em> elements with inverse orientations such as head-to-head and tail-to-tail in our minigene model. Intron retention seems to have been affected by shortening of introns or deletion of <em>Alu</em>'s splicing regulatory elements. Either way, <em>Alus</em> are associated with human gene expression incorporating themself and adopting in the human genome splicing system.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102002"},"PeriodicalIF":2.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143792722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic signatures of atheroresistance in the human atrium and ventricle highlight potential candidates for targeted atherosclerosis therapeutics","authors":"Paul A. Brown","doi":"10.1016/j.bbrep.2025.102007","DOIUrl":"10.1016/j.bbrep.2025.102007","url":null,"abstract":"<div><div>Atherosclerosis risk is not uniform throughout the cardiovascular system. This study therefore aimed to compare the transcriptomes of atheroresistant human atrium and ventricle with atheroprone coronary arteries to identify transcriptomic signatures of atheroresistance and potential targets for atherosclerosis therapeutics. Using publicly available gene read counts, differentially expressed genes between the atrium, ventricle, and coronary artery were identified for each contrast and validated against the Swiss Institute of Bioinformatics’ Bgee database. Over-representation analysis and active-subnetwork-oriented enrichment assessment then identified enriched terms, which were grouped into endothelial dysfunction-related processes. Potential biological significance was further explored with pathway analysis. Among 21474 features, 12656 differentially expressed genes were identified across the three contrasts and associated with 1215 enriched terms. There were 315 down-regulated and 133 up-regulated genes associated with endothelial dysfunction-related processes across the contrasts, including immune modulators, cell adhesion molecules, and lipid metabolism- and coagulation-related molecules. Differentially expressed genes were associated with six down-regulated Kyoto Encyclopedia of Genes and Genomes pathways, related to immune cell and associated endothelium functions. Review of regulated genes associated with endothelial dysfunction-related processes and included in these pathways, indicate immune cell-associated B cell scaffold protein with ankyrin repeats 1, as well as arterial endothelial cell-associated vascular cell adhesion molecule 1 and cadherin 5, as potential atherosclerosis targets.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102007"},"PeriodicalIF":2.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143792720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of a recombinant human TNF-α based ELISA to detect and quantify adalimumab","authors":"Dinesh Kumar Saini ,&nbsp;Manjunath S. Devaramani ,&nbsp;Hemalakshmi Shanmugavel ,&nbsp;Syeda Zuhin Tabassum ,&nbsp;Kiran Kumar Mudnakudu-Nagaraju ,&nbsp;Jalahalli Mariswamy Siddesha ,&nbsp;Radhakrishna Shetty","doi":"10.1016/j.bbrep.2025.102005","DOIUrl":"10.1016/j.bbrep.2025.102005","url":null,"abstract":"<div><div>Adalimumab, a humanized IgG1 monoclonal antibody is currently used to treat inflammatory diseases. However, a sensitive, in-house ELISA for evaluating inter- and intra-individual pharmacokinetic variability of adalimumab remains limited. In this study, an ELISA was developed to measure adalimumab levels, using recombinant human TNF-α (rhTNF-α) as capture antibody. Initially, surface plasma resonance showed acceptable binding kinetics (K_D) of 2.38x10⁻⁰⁷ nM for adalimumab. Next, a standard curve of adalimumab (1.54 ng/ml to 300 ng/ml), with five quality control points (5.2, 16, 27, 150, and 200 ng/ml) was evaluated for inter and intra-assay accuracy and precision, using serum matrix, by four independent validations. The linear range of the validated assay was 5.2 ng/ml to 200 ng/ml, upper limit of quantification (ULOQ) and lower limit of quantification (LLOQ) were 200 ng/ml and 5.2 ng/ml, respectively. The assay specificity was validated by testing cross-reactivity of rituximab with rhTNF-α, which was found to be non-reactive. Further, the hook effect was over-ruled by diluting the highest concentration of adalimumab tested to assay linear range, and dilution integrity was observed for entire concentrations within linear range (%RE ≤ 20 %), as recommended by European Medicines Agency. Collectively, this rhTNF-α binding-based ELISA method is highly sensitive, reproducible, and useful for monitoring adalimumab.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102005"},"PeriodicalIF":2.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143792721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular modeling approach in design of new scaffold of α-glucosidase inhibitor as antidiabetic drug","authors":"Fatemeh Amini,&nbsp;Khansa Ismaeal Abbas,&nbsp;Jahan B. Ghasemi","doi":"10.1016/j.bbrep.2025.101995","DOIUrl":"10.1016/j.bbrep.2025.101995","url":null,"abstract":"<div><div>Targeting α-glucosidase is essential for diabetes treatment, as it inhibits carbohydrate breakdown in the small intestine, helping to control blood glucose levels. This study aimed to design and computationally analyze sugar-based compounds as potent α-glucosidase inhibitors. We screened the BindingDB database with pharmacophore modeling in Pharmit, achieving an enrichment factor of 50.6, and evaluated ligand binding through molecular docking simulations, identifying key functional groups for optimal interactions. The compound 1b demonstrated strong inhibitory potential, binding to residues similar to those targeted by acarbose, with a GoldScore fitness of 60.57 compared to acarbose's 50.56 (IC₅₀ = 0.750 nM). A subset of compounds underwent 3D-QSAR modeling, revealing functional groups that enhance inhibitory activity, supported by high statistical quality (q² of 0.571, r² of 0.926, and F-values of 62.569 for CoMFA and 51.478 for CoMFA-RF). Based on these findings, we designed a novel scaffold through scaffold hopping, incorporating a glycosyl group to target the enzyme's active site, an amine group to improve binding affinity, and two phenyl groups that enhance inhibitory activity. Molecular docking and dynamics simulations further validated the stability and efficacy of this scaffold, showing superior interaction with α-glucosidase compared to acarbose. ADME property predictions suggested favorable pharmacokinetic properties, supporting this scaffold's potential for development as a diabetes treatment.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 101995"},"PeriodicalIF":2.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical data investigation identifies MARK3 as an oncogenic driver in castration-resistant prostate cancer","authors":"Rajnikant Raut ,&nbsp;Devesh Srivastava ,&nbsp;Vinayak Nayak ,&nbsp;Taruna Saini ,&nbsp;Parth Gupta ,&nbsp;Amit Kumar Chakraborty ,&nbsp;Chumki Choudhury ,&nbsp;Manish V. Bais ,&nbsp;Parul Mishra ,&nbsp;Ashish Misra","doi":"10.1016/j.bbrep.2025.102003","DOIUrl":"10.1016/j.bbrep.2025.102003","url":null,"abstract":"<div><div>Castration-resistant prostate cancer (CRPC) represents an aggressive and fatal form of prostate cancer that emerges following resistance to androgen deprivation therapy. Despite the availability of various drugs that can enhance the quality and prolong the survival of CRPC patients, resistance to these therapies is frequently observed, making the disease increasingly difficult to treat. Altered expression of kinases and phosphatases is a critical driver of CRPC and presents a potential target for more effective treatments. In this study, we have performed comprehensive transcriptomic analysis of ∼359 normal and CRPC patient samples from The Cancer Genome Atlas to identify the differentially expressed kinases and phosphatases in patient samples. We shortlisted the candidate genes based on their differential expression profiles, associations with patient survival, Gleason scores, and their impact on the fitness of prostate cancer cell lines. Our in-silico analysis identified microtubule affinity-regulating kinase 3 (MARK3) as a novel CRPC driver that is upregulated in CRPC patients, linked with poor survival outcomes, and affects the fitness of CRPC cells. Furthermore, we found that pharmacological inhibition of MARK3 using PCC0208017, a MARK3 inhibitor, leads to reduced cell viability, migration potential, and cell cycle arrest in the G1 phase in prostate cancer cells. Additionally, RNA sequencing analysis in 22Rv1 cells treated with the MARK3 inhibitor revealed that MARK3 influences genes involved in androgen response, epithelial-mesenchymal transition, mTOR, and myc-signalling, underscoring its pivotal role in CRPC progression. Taken together, our results establish MARK3 as a novel and promising therapeutic target in CRPC.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102003"},"PeriodicalIF":2.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive transcriptome based meta-analysis to unveil the aggression nexus of oral squamous cell carcinoma","authors":"Soujanya J. Vastrad ,&nbsp;Ganesan Rajalekshmi Saraswathy ,&nbsp;Jagadish B. Dasari ,&nbsp;Gouri Nair ,&nbsp;Ashok Madarakhandi ,&nbsp;Dominic Augustine ,&nbsp;S.V. Sowmya","doi":"10.1016/j.bbrep.2025.102001","DOIUrl":"10.1016/j.bbrep.2025.102001","url":null,"abstract":"<div><div>Lymph node metastasis in oral cancer (OC) complicates management due to its aggressive nature and high risk of recurrence, underscoring the need for biomarkers for early detection and targeted therapies. However, the drivers of this aggressive phenotype remain unclear due to the variability in gene expression patterns. To address this, an integrative meta-analysis of six publicly available transcriptomic profiles, categorized by lymph nodal status, is conducted. Key determinants of disease progression are identified through functional characterization and the TopConfects ranking approach of nodal associated differentially expressed genes (DEGs). To explore the critical nexus between lymph node metastasis and OC recurrence, significant metastatic genes were cross-analysed with literature-derived genes exhibiting aberrant methylation patterns in OC recurrence. Their clinical relevance and expression patterns were then validated in an external dataset from the TCGA head and neck cancer cohort. The analysis identified elevated expression of genes involved in extracellular matrix remodelling and immune response, while the expression of genes related to cellular differentiation and barrier functions was reduced, driving the transition to nodal positivity. The highest-ranked gene, MMP1, showed a log-fold change (LFC) of 4.946 (95 % CI: 3.71, 6.18) in nodal-negative samples, which increased to 5.899 (95 % CI: 4.80, 6.99) in nodal-positive samples, indicating consistent elevation across disease stages. In contrast, TMPRSS11B was significantly downregulated, with an LFC of −5.512 (95 % CI: −6.63, −4.38) in nodal-negative samples and −5.898 (95 % CI: −7.15, −4.64) in nodal-positive samples. Furthermore, MEIS1, down-regulated in nodal-positive status, was found to exhibit hypermethylation at CpG sites associated with OC recurrence. This study represents the first transcriptomic meta-analysis to explore the intersection of lymph node metastasis and OC recurrence, identifying MEIS1 as a potential key contributor. These comprehensive insights into disease trajectories offer potential biomarkers and therapeutic targets for future treatment strategies.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 102001"},"PeriodicalIF":2.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"‘Nelfinavir sensitizes a clinically relevant chemo-radioresistant cervical cancer in-vitro model by targeting the AKT-USP15/USP11-HPV16 E6/E7 axis","authors":"Reshma Reddy ,&nbsp;Vagmi Gaiwak ,&nbsp;Jayant Sastri Goda ,&nbsp;Tanuja Teni","doi":"10.1016/j.bbrep.2025.101987","DOIUrl":"10.1016/j.bbrep.2025.101987","url":null,"abstract":"<div><div>Resistance to standard therapies is a major challenge in managing cervical cancer, often leading to systemic relapse. This study aimed to develop an <em>in-vitro</em> model of chemo-radioresistant cervical cancer that mimics clinical conditions and also explore the therapeutic potential of the repurposed drug nelfinavir, an HIV protease inhibitor. HPV16-positive SiHa cervical cancer cells were subjected to concurrent cisplatin and ionizing radiation, to simulate the clinical treatment regimen for locally advanced cervical cancer. The resulting chemo-radioresistant subline exhibited increased IC₅₀-value, D0 dose, and a higher Resistance Index compared to parent cells, indicating resistance development. Notably, elevated HPV16 E6/E7 expression in resistant sublines suggested a role for HPV16 in resistance acquisition. Treatment with nelfinavir significantly reduced the IC₅₀-value and D0 dose in resistant cells. Additionally, exposure to nelfinavir or AKT inhibitor IV showed significant decrease in AKT, USP15, USP11 and HPV16 E6/E7 proteins. Furthermore, siRNA mediated knockdown of USP15 and USP11 in resistant cells resulted in significant reduction of HPV16 E6 and E7 oncoproteins respectively. Thus, mechanistically nelfinavir sensitized resistant cervical cancer cells by inhibiting the AKT-USP15/USP11-HPV16 E6/E7 pathway. Overall, this study successfully established a chemo-radioresistant SiHa cell model, providing a platform for investigating resistance mechanisms. It also highlights nelfinavir's potential as a therapeutic agent in overcoming chemo-radioresistance in cervical cancer.</div></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":"42 ","pages":"Article 101987"},"PeriodicalIF":2.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143769211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}