Human Genetics And Molecular Medicine - Research Publications
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Item Design, Synthesis, and Anticancer Evaluation of Hemithioindigos via Inhibition of Human Topoisomerases(John Wiley and Sons Inc, 2023-11-06T00:00:00) Kaur, Manpreet; Suman, Prabhat; Arora, Sahil; Singh, Tashvinder; Munshi, Anjana; Singh, Sandeep; Kumar, RajHemithioindigos were designed as topoisomerase inhibitors, synthesized, and evaluated for their anticancer properties against lung (A549) and breast (MDA-MB-468 and MCF7) cancer cell lines. Among all the synthetics, three compounds exerted potential anticancer effects on A549 (lung) and MCF7 (breast) cancer cell lines at low micromolar concentrations. The results revealed that two of these compounds blocked the cancer cells at the G1/S phase, while the third compound showed moderate G2/M inhibition, leading to necrotic cell death. Finally, the topoisomerase inhibition assays revealed their potent Topo I/II inhibitory actions as one of the primary anticancer mechanisms. Molecular docking studies further corroborated these findings. � 2023 Wiley-VCH GmbH.Item Assessment and identification of bioactive metabolites from terrestrial Lyngbya spp. responsible for antioxidant, antifungal, and anticancer activities(Institute for Ionics, 2023-09-09T00:00:00) Verma, Shaloo; Suman, Prabhat; Mandal, Somnath; Kumar, Roshan; Sahana, Nandita; Siddiqui, Nahid; Chakdar, HillolLyngbya from fresh and marine water produces an array of pharmaceutically bioactive therapeutic compounds. However, Lyngbya from agricultural soil is still poorly investigated. Hence, in this study, the bioactive potential of different Lyngbya spp. extract was explored. Intracellular petroleum ether extract of L. hieronymusii K81 showed the highest phenolic content (626.22 � 0.65 ?g GAEs g?1 FW), while intracellular ethyl acetate extract of L. aestuarii K97 (74.02 � 0.002 mg QEs g?1 FW) showed highest flavonoid content. Highest free radical scavenging activity in terms of ABTS�+ was recorded in intracellular methanolic extract of Lyngbya sp. K5 (97.85 � 0.068%), followed by L. wollei K80 (97.22 � 0.059%) while highest DPPH� radical scavenging activity observed by intracellular acetone extract of Lyngbya sp. K5 (54.59 � 0.165%). All the extracts also showed variable degrees of antifungal activities against Fusarium udum, F. oxysporum ciceris, Colletotrichum capsici, and Rhizoctonia solani. Further, extract of L. wollei K80 and L. aestuarii K97 showed potential anticancer activities against MCF7 (breast cancer) cell lines. GC-MS analyses of intracellular methanolic extract of L. wollei K80 showed the dominance of PUFAs with 9,12,15-octadecatrienoic acid, methyl ester, (Z,Z,Z) as the most abundant bioactive compound. On the other hand, the extracellular ethyl acetate extract of L. aestuarii K97 was rich in alkanes and alkenes with 1-hexyl-2-nitrocyclohexane as the most predominant compound. Extracts of Lyngbya spp. rich in novel secondary metabolites such as PUFAs, alkanes, and alkenes can be further explored as an alternative and low-cost antioxidant and potential apoptogens for cancer therapy. � 2023, The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.Item Natural Compound-Based Nanoparticles to Target Free Radicals in Cancer(Springer Singapore, 2022-09-28T00:00:00) Yadav, Umesh Prasad; Rhuthuparna, M.; Vasudeva, Kanika; Suman, Prabhat; Munshi, Anjana; Kumar, Santosh; Singh, SandeepCell proliferation and malignant transformation are enabled by genetic and epigenetic changes. During the malignancy process, malignant cells acquire distinguishing characteristics. Cancer cells have acquired the ability to generate more reactive oxygen species (ROS), resulting in high oxidative stress. ROS-mediated signaling is needed for cancer cell physiology, and high levels of ROS cause oxidative stress-induced cytotoxicity in cancer cells. To avoid ROS-mediated cytotoxicity, cancer cells modulate their redox state through various antioxidant mechanisms and keep their ROS levels below the threshold. Cancer treatment that targets oxidative stress is an appealing option. Many natural oxidative stress modulators and bioactive compounds have been used in the treatment of cancer. Conventional uptake of bioactive molecule is associated with lower bioavailability, solubility, unlikely biodistribution, and side effects. Traditional drug uptake is improved by nanoformulation, making it easier to overcome side effects, improve biodistribution, and extend drug duration time. Natural prooxidant-loaded nanoparticles efficiently carry prooxidant to the tumor site and selectively and efficiently induce oxidative stress-mediated cell death in cancer cells. � Springer Nature Singapore Pte Ltd. 2022.Item High levels of unfolded protein response component CHAC1 associates with cancer progression signatures in malignant breast cancer tissues(Springer Science and Business Media Deutschland GmbH, 2022-08-05T00:00:00) Mehta, Vikrant; Suman, Prabhat; Chander, HarishPurpose: The aberrant mRNA expression of a UPR component Cation transport regulator homolog 1 (CHAC1) has been reported to be associated with poor survival in breast and ovarian cancer patients, however, the expression of CHAC1 at protein levels in malignant breast tissues is underreported. The following study aimed at analyzing CHAC1 protein expression in malignant breast cancer tissues. Methods: Evaluation of CHAC1 expression in invasive ductal carcinomas (IDCs) with known ER, PR, and HER2 status was carried out using immunohistochemistry (IHC) with CHAC1 specific antibody. The Human breast cancer tissue microarray (TMA, cat# BR1503f, US Biomax, Inc., Rockville, MD) was used to determine CHAC1 expression. The analysis of CHAC1 IHC was done to determine its expression in terms of molecular subtypes of breast cancer, lymph node status, and proliferation index using Qu-Path software. Survival analysis was studied with a Kaplan�Meier plotter. Results: Immunohistochemical analysis of CHAC1 in breast cancer tissues showed significant up-regulation of CHAC1 as compared to the adjacent normal and benign tissues. Interestingly, CHAC1 immunostaining revealed high expression in tumor tissues with high proliferation and positive lymph node metastasis suggesting that CHAC1 might have an important role to play in breast cancer progression. Furthermore, high CHAC1 expression is associated with poor overall survival (OS) in large breast cancer patient cohorts. Conclusion: As a higher expression of CHAC1 was observed in tissue cores with high Ki67 index and positive lymph node metastasis it may be concluded that enhanced CHAC1 expression correlates with proliferation and metastasis. The further analysis of breast cancer patients� survival data through KM plot indicated that high CHAC1 expression is associated with a bad prognosis hinting that CHAC1 may have a possible prognostic significance in breast cancer. � 2022, The Author(s), under exclusive licence to Federaci�n de Sociedades Espa�olas de Oncolog�a (FESEO).Item Wild-type p53 suppresses formin-binding protein-17 (FBP17) to reduce invasion(Oxford University Press, 2022-01-28T00:00:00) Suman, Prabhat; Mehta, Vikrant; Craig, Andrew W. B.; Chander, HarishInvading tumor cells develop membrane protruding structures called invadopodia to invade and metastasize. Previously, we have reported the role of formin-binding protein-17 (FBP17) in extracellular matrix degradation and invadopodia formation in breast cancer cells. Here, we report a novel axis between tumor-suppressor p53 and FBP17. We observed that cell lines with mutant p53 express FBP17 to a higher level. The expression of FBP17 was reduced upon stabilizing wild-type p53. Furthermore, the immunohistochemistry analysis of breast cancer tissue microarrays demonstrated the correlation between the accumulation of p53 and enhanced FBP17 staining in invasive ductal carcinomas. The double knockdown of p53 and FBP17 showed the contribution of FBP17 in the invasion of cancer cells where p53 lost the regulatory control over FBP17. Taken together, these studies indicate that FBP17 may be a marker to understand the invasion propensity of breast cancer. � 2022 The Author(s). Published by Oxford University Press. All rights reserved.Item SNPs in miRNAs and Target Sequences: Role in Cancer and Diabetes(Frontiers Media S.A., 2021-12-02T00:00:00) Chhichholiya, Yogita; Suryan, Aman Kumar; Suman, Prabhat; Munshi, Anjana; Singh, SandeepmiRNAs are fascinating molecular players for gene regulation as individual miRNA can control multiple targets and a single target can be regulated by multiple miRNAs. Loss of miRNA regulated gene expression is often reported to be implicated in various human diseases like diabetes and cancer. Recently, geneticists across the world started reporting single nucleotide polymorphism (SNPs) in seed sequences of miRNAs. Similarly, SNPs are also reported in various target sequences of these miRNAs. Both the scenarios lead to dysregulated gene expression which may result in the progression of diseases. In the present paper, we explore SNPs in various miRNAs and their target sequences reported in various human cancers as well as diabetes. Similarly, we also present evidence of these mutations in various other human diseases. Copyright � 2021 Chhichholiya, Suryan, Suman, Munshi and Singh.Item The genomic architecture of metastasis in breast cancer: focus on mechanistic aspects, signalling pathways and therapeutic strategies(Springer, 2021-07-16T00:00:00) Chhichholiya, Yogita; Suman, Prabhat; Singh, Sandeep; Munshi, AnjanaBreast cancer is a multifactorial, heterogeneous disease and the second most frequent cancer amongst women worldwide. Metastasis is one of the most leading causes of death in these patients. Early-stage or locally advanced breast cancer is limited to the breast or nearby lymph nodes. When breast cancer spreads to farther tissues/organs from its original site, it is referred to as metastatic or stage IV breast cancer. Normal breast development is regulated by specific genes and signalling pathways controlling cell proliferation, cell death, cell differentiation and cell motility. Dysregulation of genes involved in various signalling pathways not only leads to the formation of primary tumour but also to the metastasis as well. The metastatic cascade is represented by a multi-step process including invasion of the local tumour cell followed by its entry into the vasculature, exit of malignant cells from the circulation and ultimately their colonization at the distant sites. These stages are referred to as formation of primary tumour, angiogenesis, invasion, intravasation and extravasation, respectively. The major sites of metastasis of breast cancer are the lymph nodes, bone, brain and lung. Only about 28% five-year survival rate has been reported for stage IV breast cancer. Metastasis is a serious concern for breast cancer and therefore, various therapeutic strategies such as tyrosine kinase inhibitors have been developed to target specific dysregulated genes and various signalling pathways involved in different steps of metastasis. In addition, other therapies like hyperbaric oxygen therapy, RNA interference and CRISPR/Cas9 are also being explored as novel strategies to cure the stage IV/metastatic breast cancer. Therefore, the current review has been compiled with an aim to evaluate the genetic basis of stage IV breast cancer with a focus on the molecular mechanisms. In addition, the therapeutic strategies targeting these dysregulated genes involved in various signalling pathways have also been discussed. Genome editing technologies that can target specific genes in the affected areas by making knock-in and knock-out alternations and thereby bring significant treatment outcomes in breast cancer have also been summarized. � 2021, Springer Science+Business Media, LLC, part of Springer Nature.Item Transcriptional Regulation of Pro-metastatic Protein Formin Binding Protein17 (FBP17) in Breast Cancer(Central University of Punjab, 2018) Suman, Prabhat; Chander, HarishBreast cancer is a diverse disease with multiple subtypes. Among the different molecular subtypes, triple negative breast cancers (TNBC) harbor frequent mutation in tumor suppressor p53. Recently it was shown that p53 suppresses Transducer of Cdc42-dependent Actin assembly-1 (Toca-1) that belongs to CIP4 subfamily. Members of the family including FBP17 play a significant role in actin assembly. FBP17 and Toca-1 have been recognized as key scaffolds for recruiting actin regulatory protein to promote invadopodia formation. Metastatic cancer cells form invadopodia and the F-BAR proteins are shown to enhance invadopodia. FBP17 consists of F-BAR domain, Cdc-15 homology, putative Rho-binding domain and SH3 domain. In the present study, we elucidate the correlation between p53 and FBP17 that affects metastatic potential of cancer cells. We observed that cancer cell lines with mutated p53 have high levels of FBP17. Activation of wild type p53 reduces FBP17 both at mRNA and protein level. Further, the ectopic expression of wild type p53 reduces FBP17 whereas mutant p53 failed to do so. Different cell lines and different methods of p53 activation were used to study the p53-FBP17 axis. Chromatin immunoprecipitation studies revealed the binding of p53 in the promoter of FBP17. The metastatic potential of breast cancer cells was observed after double knock down of both p53 and FBP17. Interestingly, we found that combined silencing of these two proteins led to a partial rescue of invasion upon p53 silencing in vitro. In conclusion we suggest that p53 controls FBP17 expression and FBP17 contributes to the invasion of cancer cells upon loss of p53 activity in cancer.Item Awakening the "guardian of genome": reactivation of mutant p53.(Springer, 2019) Binayke, Akshay; Mishra, Sarthak; Suman, Prabhat; Das, Suman; Chander, HarishThe role of tumor suppressor protein p53 is undeniable in the suppression of cancer upon oncogenic stress. It induces diverse conditions such as cell-cycle arrest, cell death, and senescence to protect the cell from carcinogenesis. The rate of mutations in p53 gene nearly accounts for 50% of the human cancers. Upon mutations, the conformation gets altered and becomes non-native. Mutant p53 displays long half-life and accumulates in the nucleus and interacts with oncoproteins to promote carcinogenesis and these interactions present a formidable challenge for clinicians in therapy of the disease. Variety of approaches have been developed, through which native-like function of p53 can be restored, such as restoration of the native-like structure of p53, activating the p53 family members, etc. Modern scientific techniques have led to the discovery of a variety of molecules to reactivate mutant p53 and restore its transcriptional activity. These compounds include small molecules, various peptides, and phytochemicals. In this review article, we comprehensively discuss these molecules to reactivate mutant p53 to restore the normal function with a particular focus on molecular mechanisms.Item High expression of FBP17 in invasive breast cancer cells promotes invadopodia formation(Humana Press Inc., 2018) Suman, Prabhat; Mishra, Sarthak; Chander, Harish; Suman, P.; Mishra, S.; Chander, H.Metastatic spread of the cancer is usually the consequence of the activation of signaling pathways that generate cell motility and tissue invasion. Metastasis involves the reorganization of cytoskeleton and cell shape for the swift movement of the cells through extracellular matrix. Previously, we have described the invasive and metastatic role played by one of the members (Toca-1) of CIP4 subfamily of F-BAR proteins. In the present study, we address the role of another member (FBP17) of same family in the invasion breast cancer cells. Here, we report that the formin-binding protein 17 (FBP17) is highly expressed at both mRNA and protein levels in breast cancer cells. The study showed the association of FBP17 with cytoskeletal actin regulatory proteins like dynamin and cortactin. To determine its role in extracellular matrix (ECM) degradation, we achieved stable knockdown of FBP17 in MDA-MB-231 cells. FBP17 knockdown cells showed a defect and were found to be compromised in the degradation of ECM indicating the role of FBP17 in the invasion of breast cancer cells. Our results suggest that FBP17 is highly expressed in breast cancer cells and facilitates the invasion of breast cancer cells. ? 2018, Springer Science+Business Media, LLC, part of Springer Nature.