Abstract Prostate cancer (PCa) progression is increasingly recognized as a metabolically driven process, particularly through alterations in lipid metabolism. Sterol regulatory element-binding proteins (SREBPs) are master transcription factors that regulate genes involved in lipogenesis and are often upregulated in advanced prostate cancer, leading to aberrant lipid accumulation, and are associated with poor prognosis and disease progression. Despite advances in characterizing the metabolic phenotype of PCa, a critical gap remains in understanding how SREBP-driven lipid remodeling mechanistically contributes to the metastatic dissemination of PCa. Our analysis of publicly available patient datasets revealed increased gene expression of SREBPs in prostate tumors compared to normal prostate tissue. Furthermore, we observed substantially higher SREBP gene expression in metastatic samples compared to primary tumors. We also found notably higher levels of SREBPs in the more invasive PC3M and C4-2B cell lines than in their less invasive counterparts, PC3 and LNCaP. Based on these findings, we hypothesize that inhibition of SREBPs by fatostatin could be an effective therapeutic strategy against lethal metastatic prostate cancer. We found that fatostatin inhibited the viability, proliferation, clonogenic survival, migration, and invasion of the more invasive PCa cell lines, with significantly greater potency than in less invasive lines. Immunoblotting confirmed that fatostatin inhibited both SREBPs and their downstream targets more effectively in more invasive PCa cell lines than in less invasive ones. We then performed RNA-Seq and pathway analysis on all cell lines treated with fatostatin. We found that pathways related to EMT and mTORC1 are significantly downregulated in the more invasive prostate cancer cell lines compared to their less invasive counterparts. Overall, our results demonstrate that SREBP-driven lipid metabolism mechanistically contributes to PCa invasiveness and pharmacological inhibition of SREBPs may improve outcomes in lethal metastatic prostate cancer. Citation Format: Prashanth Reddy Parupathi, Sirisha Devarakonda, Ekniel Francois, Avinash Kumar. Pharmacologic inhibition of SREBP-driven lipogenesis suppresses metastatic progression in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3145.

Abstract Prostate cancer is the foremost incident cancer and the second major cause of cancer-associated mortality among men in the U.S. Although current therapies, involving androgen receptor (AR) pathway inhibitors have improved survival rates, advanced prostate cancer remains a lethal disease. Therefore, new therapeutic approaches should continue to be investigated. Previous studies from our group as well as others have widely demonstrated the anticancer activity of resveratrol and its analogs. However, pinostilbene, a monomethylated resveratrol analog, is less well studied and reports on its anticancer activity in prostate cancer is limited. In this study, we investigated the anticancer activity of pinostilbene in prostate cancer. We found that pinostilbene inhibited the viability, proliferation, and metastatic potential of all prostate cancer cell lines tested. Of note, pinostilbene exhibited significantly higher potency as an anticancer agent in more invasive compared to less invasive prostate cancer cell lines. Overall, our results demonstrate that pinostilbene shows tremendous potential as an anticancer agent for improved management of prostate cancer. Citation Format: Ekniel Francois, Prashanth Reddy Parupathi, Sirisha Devarakonda, Avinash Kumar. Pinostilbene exhibits anticancer activity in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3147.

Abstract Androgen receptor (AR) is a well-studied nuclear transcription factor responsible for the progression of prostate cancer. Prostate Cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among men in the United States, despite the availability of advanced AR inhibitors. Hence, there is an urgent need to identify alternative therapeutic targets and agents to supplement AR-based therapy. Sterol regulatory element-binding proteins (SREBPs) are a family of transcription factors, consisting of SREBP-1 and SREBP-2, that are responsible for de novo lipogenesis and cholesterol biosynthesis. Recent studies show that crosstalk between AR and SREBP promotes PCa progression. Consistent with this, we have observed that SREBP is overexpressed in the presence of AR. Therefore, we hypothesized that pharmacological inhibition of SREBPs might be a promising therapeutic approach in androgen receptor-positive PCa. In our study, we evaluated the anticancer activity of fatostatin, an SREBP inhibitor, in AR-positive PCa cell lines (LNCaP and C4) and AR-negative PCa cell lines (PC3 and Du145). We observed inhibition of viability, proliferation, migration, and invasion in all PCa cell lines. Additionally, we observed decreased protein and mRNA expression of SREBPs and AR in the fatostatin treatment group. Notably, fatostatin showed significantly more potent inhibition in AR-positive PCa cell lines compared to AR-negative PCa cell lines. To further understand the molecular mechanism of fatostatin in AR-positive PCa cell lines, we performed RNA-Seq, which revealed inhibition of AR signaling and cholesterol homeostasis. It was also observed that genes involved in mitotic spindle assembly and the mTORC1 pathway have been downregulated. Altogether, our data show that pharmacological inhibition of SREBP may be a potential therapeutic target in AR-positive prostate cancer. Citation Format: Sirisha Devarakonda,Prashanth Parupathi,Ekniel Francois,Avinash Kumar. Targeting AR-SREBP crosstalk in prostate adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3144.

Prostate cancer (PCa), the second leading cause of cancer-related mortality among men in the United States, is marked by profound metabolic reprogramming, particularly in lipid metabolism. This review highlights the pivotal role of altered lipid metabolic pathways, including de novo fatty acid synthesis, fatty acid uptake and transport, β-oxidation, and cholesterol metabolism, in the development, progression, and therapeutic resistance of PCa. Key enzymes and transcription factors, such as FASN, ACLY, SREBPs, and FABPs, which are mainly regulated by androgen receptor signaling, orchestrate a lipogenic phenotype that supports prostate tumor growth and survival. Crosstalk between lipid metabolism and the tumor microenvironment further promotes immune evasion and metastasis. The review also explores therapeutic opportunities in targeting lipid metabolic pathways, highlighting the preclinical and clinical advances in inhibiting FASN, SREBP1, SREBP2, HMGCR, and FABPs, as well as combinatorial strategies with conventional therapies. Understanding the impact of lipid metabolism on PCa pathogenesis provides a promising avenue for developing novel targeted and combinatorial interventions to improve clinical outcomes in PCa.

In this work, ionizable and cleavable lipids were designed, synthesized, and characterized. The lipids were derived from the γ-T3 isomer of vitamin E and were used to develop novel lipid nanoparticles (LNPs) targeting Bone Marrow on X chromosome (BMX). BMX is a promising and emerging target for the development of advanced cancer therapeutics. Our team recently reported on targeting BMX using small-molecule modalities. Here, we are expanding the modality of targeting employing BMX siRNA LNPs. AI and experimental design (QbD) were used to develop an optimal formulation for the BMX siRNA delivery. AI tools helped in designing the optimal ionizable lipid and further assisted in revealing the desired interaction between the ionizable lipids and the BMX siRNA. The BXM siRNA LNPs developed in this study were initially designed based on the compositions of the FDA-approved Onpattro formulation. The vitamin E-based ionizable and cleavable lipids were synthesized and chemically characterized using 1H NMR. QbD played a crucial role in achieving the optimal formulation composition of the LNPs. The optimized BMX siRNA LNP compositions were prepared using methanol dilution and extrusion methods. The developed LNPs were characterized for their physicochemical properties, including particle size, zeta-potential, entrapment efficiency, and pH-dependent release. The in-vitro anticancer activity of the optimized BMX siRNA LPNs was also assessed. The particle size of the optimized BMX siRNA LNPs was in the range of 151 nm, with a zeta potential of 30 mV. The developed BMX siRNA LNPs exhibited a pH-dependent release profile, with the highest release occurring at an acidic pH of 5.5. The in-vitro anticancer activity of the developed BMX siRNA against two prostate cancer cell lines, DU145 and PC3, demonstrated statistically significant anticancer activity, as indicated by IC50 values of 1.1 µM and 1.3 µM, respectively, compared to the control and Onpattro-composition like formulations. Furthermore, the BMX siRNA LNP designed using the novel lipids showed a significant reduction in BMX mRNA expression levels in DU145 and PC3 cell lines compared to the control or the Onpattro-like formulation. Profoundly, the novel LNPs showed significant in-vivo anticancer activity in the Castration-Resistant Prostate Cancer (CRPC) animal model compared to control or the Onpattro-like formulation. The results from this study further support the promise of such novel LNPs in cancer therapeutics development.

Androgen receptor (AR) is a well established key biological contributor to prostate cancer progression. Despite significant efforts which have resulted in the therapeutic agents that target the AR signaling being the therapy of choice, prostate cancer remains one of the topmost causes of cancer-related deaths among men in the United States. Hence, development of novel targeted therapeutics that augment or supplant AR-based therapy remains a top priority. Sterol regulatory element binding proteins (SREBPs)are a family of transcription factors, consisting of SREBP-1 and SREBP-2, that control lipid synthesis. Available literature provides evidence for the cooperation between SREBPs and AR signaling in promoting prostate cancer progression. We observed that the SREBP expression is higher in LNCaP, C4, and C4-2 AR-positive/androgen-dependent compared to DU145, and PC3 AR-negative/androgen-independent prostate cancer cell lines. Therefore, we hypothesized that pharmacological targeting of SREBPs might be a promising therapeutic approach in hormone sensitive prostate cancer. We developed a novel boron-containing small molecule inhibitor of SREBPs, BF175, whose anticancer activity against prostate cancer has not been elucidated. In our study, we investigated the AR-dependent anticancer activity of BF175 in prostate cancer. We observed inhibition of viability, proliferation, and metastatic potential as well as induction of apoptosis in all prostate cancer cell lines treated with BF175. We also observed reduction in the levels of SREBPs in all prostate cancer cell lines treated with BF175. Notably, the anticancer action of BF175 was dependent on the AR status and BF175 demonstrated significantly more potent anticancer action in AR-positive/androgen-dependent compared to AR-negative/androgen-independent prostate cancer cell lines. Altogether, our data shows that BF175 may be a potential novel therapeutic agent for hormone sensitive prostate cancer. Lakshmi Sirisha Devarakonda, Prashanth Parupathi, Ekniel Francois, Bhasker C. Das, Avinash Kumar. AR-dependent anticancer action of BF175 in hormone sensitive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3058.

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among men in the United States. Metastasis is the major cause of mortality associated with prostate cancer, and despite the availability of targeted therapeutic agents, metastatic prostate cancer remains a lethal disease. Therefore, there is a significant unmet need to identify new drug targets and develop novel targeted therapeutic agents. Sterol regulatory element binding proteins (SREBPs) are a family of transcription factors, comprising SREBP-1 and SREBP-2, that govern lipid homeostasis by regulating the expression of numerous enzymes involved in fatty acid and cholesterol synthesis (lipogenesis). The role of SREBPs in regulating non-lipogenic transcriptional programs is beginning to be elucidated. Published findings associate perturbation of SREBP-dependent transcriptional programs in the development, progression, and metastasis of various cancers, including PCa. Our analysis of publicly available patient datasets revealed increased gene expression for SREBPs in prostate tumors compared to normal prostate. Further, we discovered significantly higher gene expression for SREBPs in metastatic samples compared to primary prostate tumors. Moreover, we found significantly elevated levels of SREBPs in more invasive PC3M and C4-2B compared to the less invasive PC3 and LNCaP prostate cancer cell lines. Hence, we hypothesized that pharmacological inhibition of SREBPs might be an effective therapeutic strategy against metastatic prostate cancer. We have developed a novel boron-containing compound, BF175, which inhibits the expression and transcriptional activity of SREBPs, but the information on the anticancer action of BF175 in various cancers, including prostate cancer, is very limited. In this study, we investigated the SREBP-mediated anticancer activity of BF175 in prostate cancer. We found that BF175 inhibited the viability, proliferation, and metastatic potential as well as induced apoptosis in all prostate cancer cell lines tested. We also confirmed that BF175 inhibited the expression of SREBPs in the tested prostate cancer cell lines. Of note, BF175 exhibited significantly higher potency as an anticancer agent in more invasive prostate cancer cell lines compared to their less invasive counterparts. Taken together, our results demonstrate that BF175 shows promise as a novel anticancer agent that may improve outcomes in lethal metastatic prostate cancer. Prashanth Parupathi, Lakshmi Sirisha Devarakonda, Enkiel Francois, Bhaskar C Das, Avinash Kumar. Targeting SREBP-driven transcriptional programs in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3050.

Supplementary Figure 1: A, transgene integration and genotyping scheme of MTA1 transgenic animals. B, genotyping of MTA1 founder 870#2. Supplementary Figure 2: A, average body weight of mice fed different diets during 22 weeks (monitored weekly). B, effect of PTER-Diet on food intake (g). Supplementary Table 1: Nutritional composition of diets. Supplementary Table 2: Primers for genotyping used in this study. Supplementary Table 3: Antibodies for immunoblots and IHC used in this study. Supplementary Table 4: Primers for qRT-PCR used in this study.

A key objective of this study was to explore the potential of dietary grape consumption to modulate adverse effects caused by a high-fat (western-pattern) diet. Female C57BL/6J mice were purchased at six-weeks-of-age and placed on a standard (semi-synthetic) diet (STD). At 11 weeks-of-age, the mice were continued on the STD or placed on the STD supplemented with 5% standardized grape powder (STD5GP), a high-fat diet (HFD), or an HFD supplemented with 5% standardized grape powder (HFD5GP). After being provided with the respective diets for 13 additional weeks, the mice were euthanized, and liver was collected for biomarker analysis, determination of genetic expression (RNA-Seq), and histopathological examination. All four dietary groups demonstrated unique genetic expression patterns. Using pathway analysis tools (GO, KEGG and Reactome), relative to the STD group, differentially expressed genes of the STD5GP group were significantly enriched in RNA, mitochondria, and protein translation related pathways, as well as drug metabolism, glutathione, detoxification, and oxidative stress associated pathways. The expression of Gstp1 was confirmed to be upregulated by about five-fold (RT-qPCR), and, based on RNA-Seq data, the expression of additional genes associated with the reduction of oxidative stress and detoxification (Gpx4 and 8, Gss, Gpx7, Sod1) were enhanced by dietary grape supplementation. Cluster analysis of genetic expression patterns revealed the greatest divergence between the HFD5GP and HFD groups. In the HFD5GP group, relative to the HFD group, 14 genes responsible for the metabolism, transportation, hydrolysis, and sequestration of fatty acids were upregulated. Conversely, genes responsible for lipid content and cholesterol synthesis (Plin4, Acaa1b, Slc27a1) were downregulated. The two top classifications emerging as enriched in the HFD5GP group vs. the HFD group (KEGG pathway analysis) were Alzheimer's disease and nonalcoholic fatty liver disease (NAFLD), both of which have been reported in the literature to bear a causal relationship. In the current study, nonalcoholic steatohepatitis was indicated by histological observations that revealed archetype markers of fatty liver induced by the HFD. The adverse response was diminished by grape intervention. In addition to these studies, life-long survival was assessed with C57BL/6J mice. C57BL/6J mice were received at four-weeks-of-age and placed on the STD. At 14-weeks-of-age, the mice were divided into two groups (100 per group) and provided with the HFD or the HFD5GP. Relative to the HFD group, the survival time of the HFD5GP group was enhanced (log-rank test, p = 0.036). The respective hazard ratios were 0.715 (HFD5GP) and 1.397 (HFD). Greater body weight positively correlated with longevity; the highest body weight of the HFD5GP group was attained later in life than the HFD group (p = 0.141). These results suggest the potential of dietary grapes to modulate hepatic gene expression, prevent oxidative damage, induce fatty acid metabolism, ameliorate NAFLD, and increase longevity when co-administered with a high-fat diet.

Apoptosis is a programmed cell death that efficiently removes damaged cells to maintain tissue homeostasis. Defect in apoptotic machinery can lead to tumor development, progression, and resistance to chemotherapy. PUMA (p53 upregulated modulator of apoptosis) and BAX (BCL2-associated X protein) are among the most well-known inducers of apoptosis. It has been reported that expression levels of BAX and PUMA are controlled at the posttranslational level by phosphorylation. However, the posttranslational regulation of these proapoptotic proteins remains largely unexplored. In this study, using biochemical, molecular biology, flow cytometric, and immunohistochemistry techniques, we show that PUMA and BAX are the direct target of the F-box protein FBXL20, which restricts their cellular levels. FBXL20 directs the proteasomal degradation of PUMA and BAX in a protein kinase AKT1-dependent manner to promote cancer cell proliferation and tumor growth. Interestingly, inactivation of AKT1 results in activation of another protein kinase GSK3 alpha/beta, which facilitates the proteasomal degradation of FBXL20 by another F-box protein, FBXO31. Thus, a switch between two signaling kinases AKT1 and GSK3 alpha/beta modulates the functional activity of these proapoptotic regulators, thereby determining cell survival or death. RNAi-mediated ablation of FBXL20 results in increased levels of PUMA as well as BAX, which further enhances the sensitivity of cancer cells to chemotherapeutic drugs. We showed that high level expression of FBXL20 in cancer cells reduces therapeutic drug-induced apoptosis and promotes chemoresistance. Overall, this study highlights the importance of targeting FBXL20 in cancers in conjunction with chemotherapy and may represent a promising anticancer strategy to overcome chemoresistance.

F-box protein 31 (FBXO31) is a reported putative tumor suppressor, and its inactivation due to loss of heterozygosity is associated with cancers of different origins. An emerging body of literature has documented FBXO31's role in preserving genome integrity following DNA damage and in the cell cycle. However, knowledge regarding the role of FBXO31 during normal cell-cycle progression is restricted to its functions during the G2/M phase. Interestingly, FBXO31 levels remain high even during the early G1 phase, a crucial stage for preparing the cells for DNA replication. Therefore, we sought to investigate the functions of FBXO31 during the G1 phase of the cell cycle. Here, using flow cytometric, biochemical, and immunofluorescence techniques, we show that FBXO31 is essential for maintaining optimum expression of the cell-cycle protein cyclin A for efficient cell-cycle progression. Stable FBXO31 knockdown led to atypical accumulation of cyclin A during the G1 phase, driving premature DNA replication and compromised loading of the minichromosome maintenance complex, resulting in replication from fewer origins and DNA double-strand breaks. Because of these inherent defects in replication, FBXO31-knockdown cells were hypersensitive to replication stress-inducing agents and displayed pronounced genomic instability. Upon entering mitosis, the cells defective in DNA replication exhibited a delay in the prometaphase-to-metaphase transition and anaphase defects such as lagging and bridging chromosomes. In conclusion, our findings establish that FBXO31 plays a pivotal role in preserving genomic integrity by maintaining low cyclin A levels during the G1 phase for faithful genome duplication and segregation.

In the last decade, strong evidence has emerged on the link between diet and epigenetic mechanisms of diseases. Dietary bioactive molecules from vegetables, fruits, and some beverages have been shown to exhibit antiinflammatory, antioxidative, and anticancer activities through multiple mechanisms including epigenetic changes associated with DNA methylation, histone modifications, and modulation of microRNAs. The epigenetic molecular mechanisms that contribute to the chemopreventive nature of dietary polyphenols have been widely studied, particularly in cancer. In addition, immunosensitization and chemosensitization properties of dietary agents make them viable candidates for combinatorial strategies leading to synergistic beneficial effects. In this chapter, we summarize current knowledge on the most studied natural products, nutrients and food components and their effects on DNA methylation, histone modifications and miRNAs in different diseases. We also provide a review on “epigenetic” clinical trials with dietary phytochemicals on disease susceptibility and their potential as epigenetic chemopreventive agents and epigenetic drugs of the future.

The aspiration of an ideal social structure includes the ambition of construction of a society that does not discriminate on the basis of gender. The development of feminist thought is an endeavor for evolutionary changes within the prevailing patriarchal society. This article exemplifies the development and changes in the feminist movement due to internal pressures, external politics, and ideological changes, by highlighting the oppression of women and the movement's chief accomplishments, and strives to explain this evolution from the standpoint of two alternative justifications, an adaptationist and by-product influence. It elucidates underlying aspects of the movement and the prerequisites for it to flourish and become a multifaceted, global phenomenon.

Metastasis associated protein 1 (MTA1) is a component of the nucleosome remodeling and deacetylating (NuRD) complex which mediates gene silencing and is overexpressed in several cancers. We reported earlier that resveratrol, a dietary stilbene found in grapes, can down-regulate MTA1. In the present study, we show that PTEN is inactivated by MTA1 in prostate cancer cells. Further, we show that resveratrol promotes acetylation and reactivation of PTEN via inhibition of the MTA1/HDAC complex, resulting in inhibition of the Akt pathway. In addition, we show that MTA1 knockdown is sufficient to augment acetylation of PTEN indicating a crucial role of MTA1 itself in the regulation of PTEN acetylation contributing to its lipid phosphatase activity. Acetylated PTEN preferentially accumulates in the nucleus where it binds to MTA1. We also show that MTA1 interacts exclusively with PTEN acetylated on Lys125 and Lys128, resulting in diminished p-Akt levels. Finally, using orthotopic prostate cancer xenografts, we demonstrate that both resveratrol treatment and MTA1 knockdown enhance PTEN levels leading to a decreased p-Akt expression and proliferation index. Taken together, our results indicate that MTA1/HDAC unit is a negative regulator of PTEN which facilitates survival pathways and progression of prostate cancer and that resveratrol can reverse this process through its MTA1 inhibitory function.

Accurate diagnosis and proper monitoring of cancer patients remain a key obstacle for successful cancer treatment and prevention. Therein comes the need for biomarker discovery, which is crucial to the current oncological and other clinical practices having the potential to impact the diagnosis and prognosis. In fact, most of the biomarkers have been discovered utilizing the proteomics-based approaches. Although high-throughput mass spectrometry-based proteomic approaches like SILAC, 2D-DIGE, and iTRAQ are filling up the pitfalls of the conventional techniques, still serum proteomics importunately poses hurdle in overcoming a wide range of protein concentrations, and also the availability of patient tissue samples is a limitation for the biomarker discovery. Thus, researchers have looked for alternatives, and profiling of candidate biomarkers through tissue culture of tumor cell lines comes up as a promising option. It is a rich source of tumor cell-derived proteins, thereby, representing a wide array of potential biomarkers. Interestingly, most of the clinical biomarkers in use today (CA 125, CA 15.3, CA 19.9, and PSA) were discovered through tissue culture-based system and tissue extracts. This paper tries to emphasize the tissue culture-based discovery of candidate biomarkers through various mass spectrometry-based proteomic approaches.