bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4319: HSF1 inhibition induces pancreatic ductal adenocarcinoma autophagy through JNK
Authors: Ghai Shruti , Young Alex , Su Kuo-Hui 
Published: March 2024

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality, with a 5-year survival rate of 12%. Chemoresistance due to autophagy, a natural process of proteotoxic stress response, is the most common chemotherapy challenge for pancreatic cancer. Autophagy, which maintains cellular homeostasis by removing damaged or unnecessary proteins and organelles, is a self-degradation process regulated by the mammalian target of rapamycin complex (mTORC1). Excessive levels of autophagy can be detrimental and lead to cell death. Nevertheless, this dual function of autophagy in regulating pancreatic cancer remains poorly understood. It has been reported that heat shock factor 1 (HSF1), a critical pro-oncogenic transcription factor in the proteotoxic stress response, inhibits c-Jun N-terminal kinase 1/2 (JNK1/2) signaling pathway to maintain mTORC1 activity and control cell size. HSF1 is highly expressed in pancreatic tumors, and inhibition of HSF1 via small molecules enhances the chemotherapy drug effect on PDAC programmed cell death. However, the PDAC autophagy response in HSF1 inhibition is currently not fully understood. Objective: The objective of this study is to investigate the molecular mechanism of HSF1 inhibition in PDAC autophagy.
Methods and Results: In human PDAC cells, Western blotting analysis revealed that HSF1 inhibition via small molecular including CCT361814/NXP800, an HSF1 inhibitor in phase I clinical trials, increased autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) lipidation and decreased expression of phosphorylation of HSF1 at Ser326 and total HSF1 protein, conversely using HSF1 overexpression model reversed this effect. Inhibition of autophagy via 3-methyladenine reversed HSF1 inhibition-induced autophagy. Results from transmission electron microscopy and GFP-LC3 reporter revealed that HSF1 inhibition induced autophagosome formation and accumulation. Furthermore, HSF1 inhibition induced phosphorylation of JNK1/2 at Thr183/Tyr185 and decreased mTORC1 activity, while knockdown JNK1/2 diminished HSF1 inhibition-induced LC3 lipidation. The combination of chemotherapy drugs with HSF1 inhibitors decreased PDAC cell viability. Additionally, blocking autophagy increased HSF1 inhibition-induced apoptosis.
Conclusions: In conclusion, JNK1/2 is involved in HSF1 inhibition-induced PDAC autophagy, targeting autophagy could unveil a novel treatment strategy for pancreatic cancer through targeted HSF1 inhibition.
Citation Format: Shruti Ghai, Alex Young, Kuo-Hui Su. HSF1 inhibition induces pancreatic ductal adenocarcinoma autophagy through JNK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4319.
Abstract 432: The noncanonical mechanism of metabolic enzyme LDHA in cancer progression
Authors: Liu Juan , Hu Wenwei , Feng Zhaohui 
Published: March 2024

Abstract
Metabolic reprogramming is a hallmark of cancer cells and a key contributor to cancer progression, which is a promising target for cancer therapies. The enhanced glycolysis, also known as the Warburg effect, represents the most widely recognized metabolic alteration in cancer, wherein the majority of cancer cells undergoes reprogramming to heavily rely on glycolysis for their accelerated growth and proliferation. The glycolytic enzyme lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate in the final stage of glycolysis. LDHA is frequently overexpressed in cancers, which plays a critical role in promoting glycolysis and cancer progression. To deepen our understanding of the oncogenic mechanism of LDHA, we screened for LDHA-interacting proteins in human breast cancer cells by liquid chromatography mass spectrometry (LC/MS) analysis. Through this strategy, small GTPase Rac1 was identified as an LDHA-interacting protein. LDHA interacted with the active form of Rac1, Rac1-GTP, and impaired the interaction of Rac1-GTP with its negative regulators, GTPase-activating proteins, leading to Rac1 activation independently of the glycolytic enzyme activity of LDHA. In addition, LDHA overexpression was significantly associated with increased Rac1 activity in clinical breast cancer specimens. Inhibiting Rac1 significantly attenuated the oncogenic effect of LDHA. Combining small-molecule inhibitors targeting LDHA enzyme activity and Rac1 activity displayed a synergistic inhibitory effect on breast cancers with LDHA overexpression in mouse models. Thus, our results revealed a novel and critical noncanonical mechanism of LDHA in promoting cancer progression through its direct interaction and activation of Rac1. Given that LDHA is frequently overexpressed in cancer, LDHA overexpression constitutes an important mechanism contributing to aberrant Rac1 activation in cancer. Importantly, our findings also suggest that pharmacologically targeting LDHA enzyme activity and Rac1 activity simultaneously is a promising strategy to treat breast cancers with LDHA overexpression.
Citation Format: Juan Liu, Wenwei Hu, Zhaohui Feng. The noncanonical mechanism of metabolic enzyme LDHA in cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 432.
Abstract 4331: Machine learning-based classification of tissue origin of cancer using methylation profiles
Authors: De Velasco Marco A. , Sskai Kazuko , Mitani Seiichiro , Kura Yurie , Minamoto Shuji , Haeno Takahiro , Hayashi Hidetoshi , Nishio Kazuto 
Published: March 2024

Abstract
Cancer of unknown primary (CUP) is a malignancy with poor prognosis and an unknown primary site and histologically unknown metastasis. Most patients receive empiric chemotherapy including platinum-taxane therapies but experience short survival times. Patients with poor prognosis CUP could benefit from optimizing drug therapy based on primary organ estimation. We constructed and evaluated an ensemble learning model to accurately determine the primary organ using methylation profiles of tumor tissues. Methylation data from 890 samples representing 10 types of cancer from TCGA were analyzed. After data preprocessing, we extracted the top 10,000 CpGs sites based on ANOVA and Gain Ratio or 100 CpG sites from a Gradient Boosting classifier. Performance was evaluated using several machine learning models. Unsupervised analysis was carried out to determine the relationships between the CpG sites selected by Gradient Boosting. Methylation profiling by ANOVA and Gain Ratio yielded favorable performance when using various machine learning models. Using gradient boosting as a feature selector reduced the number of CpG sites by 100-fold without compromising model performance. The training and validation sets showed favorable results for the classification of primary organs with ensemble models. In validation, classification accuracy was 91.2%, 93.5%, 89.7%, and 87.7% for Extreme Gradient Boosting, CatBoost, Random Forest, and Gradient Boosting, respectively. Further profiling of the selected methylation regions was correlated with cancer types and even revealed subgroups within breast and lung cancers. Gradient Boosting as a feature selector for DNA methylation profiling was highly effective in accurately determining tissue origin. Our study has outlined an approach whereby we used an embedded machine learning algorithm to identify a select set of informative features from complex high-dimension data to train and predict cancer type.
Citation Format: Marco A. De Velasco, Kazuko Sskai, Seiichiro Mitani, Yurie Kura, Shuji Minamoto, Takahiro Haeno, Hidetoshi Hayashi, Kazuto Nishio. Machine learning-based classification of tissue origin of cancer using methylation profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4331.
Abstract 4364: Molecular insight of non-canonical Gsk3β-Gli-AR axis: Therapeutic implications of truncated-Gli3 in castration-resistant prostate cancer
Authors: Kaushal Jyoti Bala , Raut Pratima , Seshacharyulu Sarathy , Alsafwani Zahraa W. , Sharma Gunjan , Khan Abdullah M. , Halder Sushanta , Rachagani Satyanarayana , Batra Surinder K. , Siddiqui Jawed A. 
Published: March 2024

Abstract
The aberrant activation of the hedgehog (Hh) signaling pathway causes the progression of therapy-resistant castration-resistant prostate cancer (CRPC). In this study, we aimed to unravel the biological significance of Gli-family proteins and their functional involvement of Gsk3β-mediated regulatory mechanism(s) in CRPC. We have discovered a novel function of the truncated form of Gli (t-Gli3) in advancing CRPC. This was accomplished through in silico analysis, in vitro experiments, PCa patient clinical data, and in vivo PCa MYC overexpression mouse models. Our investigation into the Gli3 regulation, typically influenced by receptor-mediated ciliary localization, uncovered a Smo-independent mechanism. Surprisingly, despite the lack of a transactivation domain in t-Gli3, we found a specific requirement for an androgen receptor variant 7 (AR-V7) for its action, as evidenced by co-immunoprecipitation and chromatin immunoprecipitation assays. Mechanistically, Gsk3β activation leads to the t-Gli3 generation, and inhibition of Gsk3β supported the accumulation of full-length Gli3 through a non-canonical mechanism. Knockdown of Gsk3β (Gsk3β KD) reduces CRPC cell proliferation in 2-D and 3-D culture models, inhibiting key proliferative signaling pathways and inducing apoptosis via mitochondrial fragmentation. These findings were supported using an orthotropic PCa mouse model. RNA-seq analysis also showed upregulated phenotype enrichment of the apoptosis, P53, and glycolysis pathway genes in 22Rv1Gsk3β KD cells. Compared to scramble, a lower OCR/mitochondrial respiratory rate is evident in 22Rv1Gsk3β KD cells. Next, our exploration of potential therapies for PCa showed that individually targeting Smo or Gli1 is insufficient to inhibit cell viability. Interestingly, we uncovered that solely targeting Gli3 was sufficient to inhibit the growth of CRPC cells. In conclusion, our study provides the significance of Gli-family proteins and novel insights into the interplay of Gsk3β, t-Gli3, and AR, offering therapeutic implications in CRPC.
Citation Format: Jyoti Bala Kaushal, Pratima Raut, Sarathy Seshacharyulu, Zahraa W. Alsafwani, Gunjan Sharma, Abdullah M. Khan, Sushanta Halder, Satyanarayana Rachagani, Surinder K. Batra, Jawed A. Siddiqui. Molecular insight of non-canonical Gsk3β-Gli-AR axis: Therapeutic implications of truncated-Gli3 in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4364.
Abstract 4372: Epithelial-to-mesenchymal transition-driven secretory program underlies vulnerabilities in lung cancer
Authors: Fulp Kevin L. , Obaleye Oluwafunminiyi E. , Xiao Guan-Yu 
Published: March 2024

Abstract
Epithelial-to-mesenchymal transition (EMT) is a driving force behind lung adenocarcinoma (LUAD) progression. Although substantial evidence has been attained in the involvement of EMT and its regulatory mechanisms in cancer, few effective EMT-targeted therapies have been available in the clinic thus far. It is urgent to develop new therapeutic strategies for improving patient outcomes. We have identified RAB6A as a master regulator of EMT-driven secretory trafficking, which coordinates cancer cell invasion and immunosuppression in LUAD. We found that RAB6A expression was associated with a poor prognosis in LUAD patients and that RAB6A inhibition in our LUAD models reversed resistance to immune checkpoint inhibition with PD-L1 blockade, an emerging clinical problem. Thus, RAB6A machinery is a therapeutic target of interest in EMT-driven cancers. Screening approaches to identify selective RAB inhibitors are in their infancy, a challenge that can be overcome only by obtaining insights into the regulation of RAB6A. RAB6A is a small GTPase whose activity is controlled by guanine nucleotide exchange factors (GEFs) like RIC1 and RGP1, and GTPase activating proteins (GAPs) like RABGAP1, as well as other effector proteins. While these GEFs, GAPs, and effectors are all known regulators of RAB6A function and are frequently amplified in different cancer types, their specific functions in cancer progression are still unknown. To establish the causal relationship between these proteins and EMT-driven LUAD progression, we utilize human and murine LUAD cell lines that have been characterized with respect to EMT status. Our findings here show that the intervention of RAB6A activity via depletion of these regulators impairs the recruitment of RAB6A to the Golgi. We demonstrate that knocking down the GEFs, RIC1 and RGP1, significantly decreases invasion while having negligible effects on the migrative and proliferative abilities of these cells. RABGAP1 depletion, on the other hand, reduces cell proliferation but has no effects on the migration and invasion of the cells. Consistent with these results, inactivation of RAB6A abolishes the EMT-dependent pro-metastatic secretion. Mechanistically, the EMT activator, ZEB1, upregulates RGP1 via silencing miR-148a that targets this GEF to activate RAB6A. These findings elucidate the regulatory mechanisms underlying the EMT-driven secretory program, providing a foundation for therapeutic intervention to prevent the progression of LUAD.
Citation Format: Kevin L. Fulp, Oluwafunminiyi E. Obaleye, Guan-Yu Xiao. Epithelial-to-mesenchymal transition-driven secretory program underlies vulnerabilities in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4372.
Abstract 4377: AT rich interaction domain 5a promotes gastrointestinal tumorigenesis by regulating YAP and STAT3 pathways
Authors: Taniguchi Koji , Hamada Kazuya , Tanaka Shugo , Kurosu Hiroyuki , Kawakita Issei , Kumagai Kentaro , Nakazono Kentaro , Iwasaki Sari , Tanaka Satoshi 
Published: March 2024

Abstract
Background: Chronic inflammation and an inflammatory cytokine, interleukin(IL)-6, play important roles in gastrointestinal tumorigenesis and metastasis. Recently, autocrine IL-6 has been reported to promote cancer development and progression in gastrointestinal cancer. However, it is still unknown how IL-6 level is regulated in gastrointestinal cancer cells. RNA-binding proteins (RBPs) are known to be one of the regulatory mechanisms of cytokine production, including IL-6, especially in immune cells. AT rich interaction domain 5a (Arid5a), one of the RBPs, has been reported to bind to IL6 3’UTR and regulates its stability and expression. Therefore, we aimed to elucidate the role of Arid5a in gastrointestinal cancer, especially gastric and colon cancer.
Methods: Human gastric and colon cancer cell lines were used in this study. Arid5a knocked-down gastric and colon cancer cells were generated with lentiviral transduction of shRNAs targeting Arid5a and their phenotypes were investigated by several assays including MTT, apoptosis and sphere formation assays. Bulk RNA-seq analysis was performed using Arid5a knocked-down gastric and colon cancer cells.
Results: In both human gastric and colon cancer cell lines, Arid5a knockdown suppressed cancer cell proliferation and spheroid formation, and increased apoptosis. Unexpectedly, IL6 mRNA expression was not correlated with Arid5a expression level. We found that Arid5a knockdown suppresses the activation of YAP and STAT3 by western blot analysis. We identified several new Arid5a target genes by bulk RNA-seq analysis.
Conclusion: Arid5a plays an important role in the regulation of cancer cell proliferation, apoptosis and stemness in human gastric and colon cancer cells, perhaps independently of IL-6. Arid5a regulates YAP and STAT3 pathways by unknown mechanisms. We are now investigating how Arid5a regulates YAP and STAT3 pathways by focusing new Arid5a target genes.
Citation Format: Koji Taniguchi, Kazuya Hamada, Shugo Tanaka, Hiroyuki Kurosu, Issei Kawakita, Kentaro Kumagai, Kentaro Nakazono, Sari Iwasaki, Satoshi Tanaka. AT rich interaction domain 5a promotes gastrointestinal tumorigenesis by regulating YAP and STAT3 pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4377.
Abstract 4379: RING1, a novel E3 ubiquitin ligase for CIP2A, negatively regulates smoking-induced lung tumorigenesis
Authors: Jeong In-ho , Lee Chang-Whan Peter , Lim Hwan Jung , Park Seong Jun , Hyun Ji Young 
Published: March 2024

Abstract
Lung cancer is the second incidence rate of all new cancer diagnoses and the leading cause of cancer-related deaths globally. To develop novel diagnostic and therapeutic targets for lung cancer, there are emerging needs for molecular biological research on the occurrence and progression. Among the targets, CIP2A has been studied for promoting various cancer types, but detailed underlying mechanisms are needed to be further investigated. In this study, it was verified that CIP2A is overexpressed in lung cancer tissues, particularly amongst those with a smoking history, compared to adjacent normal tissues. CIP2A knockdown in lung cancer cells efficiently reduced cell proliferation and migration capacity. Through the mass spectrometry analysis on A549 cells overexpressing CIP2A, RING1 was identified as a candidate for E3 ligase of CIP2A. The interaction of the two proteins and ubiquitin chain regulation by RING1 was verified by immunoprecipitation. RING1 knockdown enhanced proliferation and migration of lung cancer cells, and these effects result from the upregulation of CIP2A and its downstream molecules, c-Myc and cyclin B1. To further study a trigger for RING1 expression changes in lung tumorigenesis, cigarette smoke extract (CSE) was applied for the following experiments. CSE treatment depleted RING1 mRNA, including protein expression. Decreased RING1 level led to upregulation of CIP2A and c-MYC. Collectively, these results reveal novel roles of the RING1 and CIP2A in lung cancer progression caused by smoking and propose a potential biomarker candidate for the therapeutic and diagnostic targets.
Citation Format: In-ho Jeong, Chang-Whan Peter Lee, Hwan Jung Lim, Seong Jun Park, Ji Young Hyun. RING1, a novel E3 ubiquitin ligase for CIP2A, negatively regulates smoking-induced lung tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4379.
Abstract 439: Tackling oxidative phosphorylation of glioblastoma stem cells through the specific impairment of transmembrane chloride intracellular channel 1
Authors: Cianci Francesca , Verduci Ivan , Cazzoli Riccardo , Minucci Saverio , Mazzanti Michele 
Published: March 2024

Abstract
Solid cancer cells show higher energy and biomolecules requirements compared with healthy cells, making the targeting of cancer metabolic dysfunctions an appealing therapeutic approach. Tackling the tumor metabolism is a daunting task, due to the ability of cancer cells to re-organize their metabolism switching between glycolysis and oxidative phosphorylation. Cancer metabolic plasticity and re-programming is partially supported by altered ionic channels expression and activity. Our laboratory has described the chronic presence transmembrane form of Chloride Intracellular Channel 1 (tmCLIC1) as a marker of malignancy in tumor cells and a possible therapeutic target since it is mainly absent in healthy cells. CLIC1 is described as a metamorphic protein able to shuttle between the cytoplasmic form to a transmembrane conformation. In the present investigation, we show that tmCLIC1 acts as a privileged metformin target in glioblastoma stem-like cells. Metformin is the first-line drug for type 2 diabetes and has been proposed as an antineoplastic drug, but no direct evidence of its’ membrane permeability nor of a specific membrane receptor in cancer cells has been found yet. Here we demonstrate that metformin impairs tmCLIC1 activity by direct and specific binding coordinated by arginine 29. This residue mutation prevents metformin from tmCLIC1 binding and abolishes the drug's effect on glioblastoma cells in 2D and 3D models and its actions on mitochondrial respiration. In vivo experiments in zebrafish embryos and mice orthotopically engrafted with glioblastoma cells and treated with metformin have shown that metformin binding to tmCLIC1 is crucial for its anti-neoplastic effect.
Citation Format: Francesca Cianci, Ivan Verduci, Riccardo Cazzoli, Saverio Minucci, Michele Mazzanti. Tackling oxidative phosphorylation of glioblastoma stem cells through the specific impairment of transmembrane chloride intracellular channel 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 439.