Browsing by Author "Chander, Harish"

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Awakening the "guardian of genome": reactivation of mutant p53.
(Springer, 2019) Binayke, Akshay; Mishra, Sarthak; Suman, Prabhat; Das, Suman; Chander, Harish
The 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.
Biomedical applications of L-alanine produced by Pediococcus acidilactici BD16 (alaD +)
(Springer Science and Business Media Deutschland GmbH, 2022-01-28T00:00:00) Sharma, Anshula; Mehta, Vikrant; Rani, Suman; Noda, Masafumi; Sugiyama, Masanori; Chander, Harish; Kaur, Baljinder
Abstract: L-alanine possesses extensive physiological functionality and tremendous pharmacological significance, therefore could be considered as potential ingredient for food, pharmaceutical, and personal care products. However, therapeutic properties of L-alanine still need to be addressed in detail to further strengthen its utilization as a viable ingredient for developing natural therapeutics with minimum side effects. Thus, the present study was aimed to explore the anticipated therapeutic potential of L-alanine, produced microbially using a lactic acid bacterial strain Pediococcus acidilactici BD16 (alaD+) expressing L-alanine dehydrogenase enzyme. The anticipated therapeutic potential of L-alanine was assessed in terms of anti-proliferative, anti-bacterial, and anti-urolithiatic properties. Anti-bacterial assays revealed that L-alanine successfully inhibited growth and in vitro proliferation of important human pathogens including Enterococcus faecalis, Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus, Streptococcus mutans, and Vibrio cholerae in a concentration-dependent manner. Current investigation has also revealed its significant anti-proliferative potential against human lung adenocarcinoma (A549; IC50 7.32�?M) and mammary gland adenocarcinoma (MCF-7; IC50 8.81�?M) cells. The anti-urolithiatic potential of L-alanine was augmented over three different phases, viz., nucleation inhibition, aggregation inhibition, and oxalate depletion. Further, an in vitro cell culture�based kidney stone dissolution model using HEK293-T cells was also established to further strengthen its anti-urolithiatic potential. This is probably the first in vitro cell culture�based model which experimentally validates the immense therapeutic efficacy of L-alanine in treating urolithiasis disease. Key points: � Assessment of therapeutic potential of L-alanine produced by LAB. � L-alanine exhibited significant anti-proliferative and anti-bacterial activities. � L-alanine as potential anti-urolithiatic agent. � 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Cancer informatics analysis indicates high CHAC2 associated with unfavorable prognosis in breast cancer
(Frontiers Media S.A., 2022-12-09T00:00:00) Chand, Subhash; Mehta, Vikrant; Sharma, Ratnesh K.; Anvikar, Anupkumar R.; Chander, Harish
Breast cancer remains the most commonly diagnosed cancer worldwide and exhibits a poor prognosis. The induction of genetic changes deregulates several genes that increase the disposal towards this life-threatening disease. CHAC2, a member of the glutathione degrading enzyme family has been shown to suppress gastric and colorectal cancer progression, however, the expression of CHAC2 in breast cancer has not been reported. We did an analysis of CHAC2 expression in breast cancer patients from various online tools like UALCAN, GEPIA2, GENT2, TIMER2, and bcGenExminer v4.8. Further, we used the Kaplan-Meier plotter to establish the significance of CHAC2 in BC patient survival and prognosis while TISIDB and TIMER databases were used to investigate the filtration of immune cells. The results showed that CHAC2 levels were high in breast cancer patients and elevated CHAC2 was associated with low overall survival. Taken together, the results of the present study show that like its paralog CHAC1, CHAC2 may also be an important biomarker and could have a potential therapeutic implication in breast cancer. Copyright � 2022 Chand, Mehta, Sharma, Anvikar and Chander.
CIP4 promotes metastasis in triple-negative breast cancer and is associated with poor patient prognosis
(Impact Journals, 2015) Cerqueira, Otto L.D.; Truesdell, Peter; Baldassarre, Tomas; Vilella-Arias, Santiago A.; Watt, Kathleen; Meens, Jalna; Chander, Harish; Os-rio, Cynthia A.B.; Soares, Fernando A.; Reis, Eduardo M.; Craig, Andrew W.B.
Signaling via epidermal growth factor receptor (EGFR) and Src kinase pathways promote triple-negative breast cancer (TNBC) cell invasion and tumor metastasis. Here, we address the role of Cdc42-interacting protein-4 (CIP4) in TNBC metastasis in vivo, and profile CIP4 expression in human breast cancer patients. In human TNBC cells, CIP4 knock-down (KD) led to less sustained activation of Erk kinase and impaired cell motility compared to control cells. This correlated with significant defects in 3D invasion of surrounding extracellular matrix by CIP4 KD TNBC cells when grown as spheroid colonies. In mammary orthotopic xenograft assays using both human TNBC cells (MDA-MB-231, HCC 1806) and rat MTLn3 cells, CIP4 silencing had no overt effect on tumor growth, but significantly reduced the incidence of lung metastases in each tumor model. In human invasive breast cancers, high CIP4 levels was significantly associated with high tumor stage, TNBC and HER2 subtypes, and risk of progression to metastatic disease. Together, these results implicate CIP4 in promoting metastasis in TNBCs.
Eeffect of Natural Compounds on Her2 Expression
(Central University of Punjab, 2018) Uradanda, Praveen; Chander, Harish
Breast cancer is a heterogeneous disease that is challenging to treat.we examine potential natural compounds which may help in treating her2 positive breast cancer. The main objectives of this study are to determine the mRNA level and protein levels on exposing MDAMB453 cell lines with Quercetin and PEITC at 40µm,44hrs.we have found in result analysis that her2 expression is downregulated on treatment with PEITC.where cell line treated with quercetin as no effect to downregulate her2 expression in MDAMB453.
Effect of TiO2 and Fe doped TiO2 nanoparticles on mitochondrial membrane potential in HBL-100 cells
(American Institute of Physics, 2019) Barkhade, T; Mishra, S; Chander, Harish; Mahapatra, S.K; Banerjee, I.
Titanium dioxide (TiO2) nanoparticles (NPs) have made unbelievable progress in the field of nanotechnology and biomedical research. The proper toxicological assessment of TiO2 NPs and the reduction of its cytotoxicity need to be addressed. Fe doping in TiO2 has been investigated to reduce the toxic effects of TiO2 NPs. Fe doped TiO2 powder samples were synthesized by sol-gel methods. The prepared samples were characterized by x-ray diffractometer (XRD), transmission electron microscope (TEM), and Raman spectroscopy to study their structure, morphology, and molecular conformation. XRD results revealed the coexistence of anatase (A) and rutile (R) phases of TiO2. The A-R transformation was observed with an increase in Fe doping along with the formation of α-Fe2O3 phase. TEM showed changes in morphology from spherical nanoparticles to elongated rod-shaped nanostructures with increasing Fe content. Shape variation of TiO2 nanoparticles after incorporation of Fe is a key reason behind the toxicity reduction. The authors observed that the toxicity of TiO2 nanoparticles was rescued upon Fe incorporation. The effect of NPs on the mitochondrial membrane potential (MMP) was assessed using flow cytometry. The MMP (%) decreased in TiO2 treated cells and increased by 1% Fe doped TiO2 NPs treated cells. Confocal imaging revealed the presence of functional mitochondria upon the exposure of Fe doped TiO2 NPs. The goal of the present study was to decrease the toxic effects induced by TiO2 NPs on mitochondrial potential and its prevention by Fe doping. © 2019 Author(s).
Expression of CHAC1 in Breast Cancer Cell Lines
(Central University of Punjab, 2018) Sharma, Ankita; Chander, Harish
Breast cancer is the commonly diagnosed type of cancer in women and is a major cause of deaths in women. Unfolded Protein Response Pathway is a signaling pathway induced in endoplasmic reticulum as a stress response. This type of stress signaling has been seen to be activated in many tumors including breast cancer. CHAC1 (Glutathione specific gamma- glutamylcyclotransferas-1) is a member of UPR Pathway. It was first discovered as a component of the ATF4 arm of the UPR pathway in a co-regulated group of genes. CHAC1 expression is necessary and sufficient to induce well-characterized markers of apoptosis. CHAC1 is involved in the inhibition of TNFRS6B via ATF4-ATF3-CHOP signaling. This sensitizes cells to commit to apoptosis following induction of UPR pathway. Although CHAC1 is a pro-apoptotic component of the UPR pathway, its expression in breast cancers have been noted to be remarkably high. To study the role of CHAC1 in breast cancer, we analyzed the expression of CHAC1 at mRNA level by using Real-Time PCR and further checked its' protein expression by Western-blotting. Its expression was found to be higher in ER positive cells as compared to the ER negative cells. Further investigations were performed by transfecting MDA-MB-231 cells by ER-alpha, which confirmed that presence of ER-alpha leads to the higher expression cHAC1 in breast cancer cells.
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.
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, Harish
Purpose: 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).
KIBRA Team Up with Partners to Promote Breast Cancer Metastasis
(Springer, 2019) Singh G; Mishra, S; Chander, Harish
Among women, breast cancer is the most frequently diagnosed cancer. Most of the breast cancers represent metastasis to distant organs at the time of diagnosis and accounts for the majority of deaths. Metastasis is characterized by many genetic aberrations including mutations, overexpression of oncogenes etc. KIBRA (KIdney/BRAin protein), a scaffolding protein is recently described as an important player in the process of invasion and metastasis. The Kidney/BRAin protein through its different domains interacts with various proteins to couple cytoskeleton arrangement, cell polarity and migration. N terminal and C terminal of the protein contains the WW, Internal C 2 & putative class III PDZ domain that interacts with DDR1, DLC1 & PKCζ. These protein-protein interactions equip the breast cancer cells to invade and metastasize. Here, we discuss a comprehensive knowledge about the KIBRA protein, its domains and the interacting partners involved in metastasis of breast cancer. © 2019, Arányi Lajos Foundation.
Mechanisms of Anti-Tumor Activity of Withania somnifera (Ashwagandha)
(Routledge, 2020-06-17T00:00:00) Mehta, Vikrant; Chander, Harish; Munshi, Anjana
Increasing herbal formulations have been used to treat several diseases including cancer. W. somnifera (Ashwagandha) is one such plant the extracts of which have been tested against a number of ailments including cancer, which remains as one of the most dreadful diseases on the globe. The ever-increasing number of cancer related mortality demands the development of novel chemopreventive agents with minimum side effects. Different compounds isolated from various parts of the plant like root, stem, and leaves have been reported to display significant anti-cancerous and immunomodulating properties and thus can be used alone or in combination with other chemotherapeutic drugs for cancer treatment. Through this review, we highlight the importance of W. somnifera in countering the potential oncogenic signaling mediators that are modulated by active constituents of W. somnifera in a variety of cancer types. Further, we hope that active constituents of W. somnifera will be tested in clinical trials so that they can be used as an important adjuvant in the near future for the effective treatment of cancer. � 2020 Taylor & Francis Group, LLC.
Prognostic significance of CHAC1 expression in breast cancer
(Springer Science and Business Media B.V., 2022-06-21T00:00:00) Mehta, Vikrant; Meena, Jaipal; Kasana, Harit; Munshi, Anjana; Chander, Harish
Background: An emerging component of Unfolded Protein Response (UPR) pathway, cation transport regulator homolog 1 (CHAC1) has been conferred with the ability to degrade intracellular glutathione and induce apoptosis, however, many reports have suggested a role of CHAC1 in cancer progression. Our study aimed to investigate CHAC1 mRNA levels in large breast cancer datasets using online tools and both mRNA and protein levels in different breast cancer cell lines. Methods and results: Analysis of clinical information from various online tools (UALCAN, GEPIA2, TIMER2, GENT2, UCSCXena, bcGenExMiner 4.8, Km Plotter, and Enrichr) was done to elucidate the CHAC1 mRNA expression in large breast cancer patient dataset and its correlation with disease progression. Later, in vitro techniques were employed to explore the mRNA and protein expression of CHAC1 in breast cancer cell lines. Evidence from bioinformatics analysis as well as in vitro studies indicated a high overall expression of CHAC1 in breast tumor samples and had a significant impact on the prognosis and survival of patients. Enhanced CHAC1 levels in the aggressive breast tumor subtypes such as Human Epidermal growth factor receptor 2 (HER2) and Triple Negative Breast Cancer (TNBC) were evident. Our findings hint toward the possible role of CHAC1 in facilitating the aggressiveness of breast cancer and the disease outcome. Conclusion: In summary, CHAC1 is constantly up-regulated in breast cancer leading to a poor prognosis. CHAC1, therefore, could be a promising candidate in the analysis of breast cancer diagnosis and prognosis. � 2022, The Author(s), under exclusive licence to Springer Nature B.V.
Psychological Burden Faced By Vitiligo Patients: A Comparative Study In Kerala And Punjab
(Central University of Punjab, 2018) G, Ameetha; Chander, Harish
Vitiligo is a common chronic skin disease having unknown aetiology, which causes a disfigurement and variable amount of skin and hair depigmentation and may affect a patient?s quality of life. To assess the psychological burden and epidemiologic profile of various age groups of patients affected by vitiligo in the southernmost district of the coastal state of Kerala and southern part of Punjab. All were investigated in a door- to- door survey. The questionnaire consisted of two sections, including psychological burden and their epidemiologic profile of various age groups. The questionnaire assigned contained questions about vitiligo characteristics such as the body surface area affected, skin tone, affected by genital vitiligo or not, marriage life and their sexual relationship, stigmatised conditions facing, whether or not affected areas were covered by dresses. 40% of males and 60 % of females were affected by vitiligo in Kerala but in Punjab males were more affected than females i.e. 60% and 40% respectively. The present study revealed that in Kerala and Punjab 25% of vitiligo patients were reported within the age group of 51-60 years and 20% within the age group of 21-30 years. More than 25% patients in Kerala and Punjab were fully affected with the vitiligo and the quality of life was impaired more in those patients and to a greater extent in women is more seen. About 76% of patients admitted of feeling self-conscious about their skin in Kerala whereas in Punjab 24% were affected.
Recent advances in HER2 positive breast cancer epigenetics: Susceptibility and therapeutic strategies
(Elsevier Masson SAS, 2017) Singla, Heena; Ludhiadch, Abhilash; Kaur, Raman Preet; Chander, Harish; Kumar, Vinod; Munshi, Anjana
HER2 amplification/overexpression accounts for aggressive clinical features of HER2 positive breast cancer. Epigenetic changes including DNA methylation, histone modifications and ncRNAs/miRNAs are associated with regulation of DNA chromatin and specifically, gene transcription. Hence, these produce eminent effects upon proto-oncogenes, tumor-suppressors and key cancer-regulatory signaling pathways. Understanding of epigenomic regulation of HER2 overexpression and signaling may help uncover the unmatchable physiology of HER2 gene/protein. Moreover, this may also aid in resolving the major issue of resistance-development towards HER2 targeted agents (trastuzumab and lapatinib), since epigenetic alterations are important therapeutic markers and modulate the response towards HER2 targeted therapy. Therefore, in this review the information regarding various epigenetic markers implicated in HER2 positive breast cancer susceptibility and therapeutic-strategies has been compiled. ? 2017 Elsevier Masson SAS
Study the effect of phytochemicals phenethyl isothiocyanate (PEITC) and Quercetin on mitochondrial biogenesis in cancer and normal cell lines
(Central University of Punjab, 2018) Thakur, Anchal; Chander, Harish
Phytochemicals are plant-derived chemicals generally are biologically active compounds and mediate positive health benefits by targeting genes or metabolic pathways of a cell. The phytochemicals examined can be classified into main categories, such as carotenoids and polyphenols, which include phenolic acids, flavonoids and stilbenes / lignans. Quercetin is isolated from the Tridax procumbens (Linn.). Its anti-cancer activity has been well documented in vitro and in vivo. It could be pro-apoptotic as well as anti-apoptotic depending upon its concentration of it and time of exposure. Isothiocyanates are cruciferous derived phytochemicals. PEITC majorly isolated from Nasturtium officinale (watercress) has shown to mediate its anti-cancer activity through ROS-mediated pathway. It is a basic leucine zipper protein involved in protection against oxidative damage triggered by stress like injury or inflammation through regulation of the expression of anti- oxidant proteins. Under oxidative stress, inactivation of Kelch-like ECH-associated protein 1 (Keap1) occurs which is a cytosolic repressor protein that binds to Nrf2. This results in Nrf2-Keap1 complex dissociation, and hence, promoting the translocation of Nrf2 to the v nucleus where it binds to ARE (anti-oxidant response element), and induce the transcription of anti-oxidative proteins. Quercetin and PEITC treatment to the cancer cells led to decreased mitochondrial biogenesis as the NRF-2 levels diminishes as the concentration of the drug increases. The anti-oxidant levels are getting down in the cancer cells leading to ROS accumulation in the cancer cells leading ultimately to the death. Quercetin and PEITC treatment to the normal HBL-100 cells induced the mitochondrial biogenesis by increasing NRF-2 levels as the concentration of the drug increases. Confocal microscopy results also proved that treatment of quercetin or PEITC or the combination of both drugs was found to be effective in cancer cells as the mitochondria size and shape got decreased interpreted through the intensity of green dye. To conclude our study, it has been shown that quercetin and PEITC lead to increased mitochondrial biogenesis in normal cells whereas decreased mitochondrial biogenesis in cancer cells.
Toca-1 is suppressed by p53 to limit breast cancer cell invasion and tumor metastasis
(BioMed Central Ltd., 2014) Chander, Harish; Brien, Colin D; Truesdell, Peter; Kathleen, Watt; Meens, Jalna; Schick, Colleen; Germain, Doris; Craig, Andrew WB
Introduction: Transducer of Cdc42-dependent actin assembly-1 (Toca-1) recruits actin regulatory proteins to invadopodia, and promotes breast tumor metastasis. Since metastatic breast tumors frequently harbor mutations in the tumor suppressor p53, we tested whether p53 regulates Toca-1 expression. Methods: Normal mammary epithelial cells (HBL-100, MCF10A) and breast cancer cell lines expressing wild-type (WT) p53 (DU4475, MTLn3) were treated with camptothecin or Nutlin-3 to stabilize p53 to test effects on Toca-1 mRNA and protein levels. Chromatin immunoprecipitation (ChIP) assays were performed to identify p53 binding site in Toca-1 gene. Stable silencing of p53 and Toca-1 were performed in MTLn3 cells to test effects on invadopodia and cell invasion in vitro, and tumor metastasis in vivo. Results: We observed that breast cancer cell lines with mutant p53 have high levels of Toca-1 compared to those with WT p53. Stabilization of WT p53 led to further reduction in Toca-1 mRNA and protein levels in normal breast epithelial cells and breast cancer cells. ChIP assays revealed p53 binding within intron 2 of toca1, and reduced histone acetylation within its promoter region upon p53 upregulation or activation. Stable silencing of WT p53 in MTLn3 cells led to increased extracellular matrix degradation and cell invasion compared to control cells. Interestingly, the combined silencing of p53 and Toca-1 led to a partial rescue of these effects of p53 silencing in vitro and reduced lung metastases in mice. In human breast tumors, Toca-1 levels were high in subtypes with frequent p53 mutations, and high Toca-1 transcript levels correlated with increased risk of relapse. Conclusions: Based on these findings, we conclude that loss of p53 tumor suppressor function in breast cancers leads to upregulation of Toca-1, and results in enhanced risk of developing metastatic disease. ? Chander et al.
Transcriptional Regulation of Pro-metastatic Protein Formin Binding Protein17 (FBP17) in Breast Cancer
(Central University of Punjab, 2018) Suman, Prabhat; Chander, Harish
Breast 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.
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, Harish
Invading 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.