KLF17 attenuates estrogen receptor α-mediated signaling by impeding ERα function on chromatin and determines response to endocrine therapy.

Luminal-like breast cancer expressing estrogen receptor α (ERα) is among the aggressive breast tumor subtypes and shows poor prognosis. KLF17 plays a key role in breast cancer inhibition. However, the underlying mechanisms by which KLF17 control breast cancer progression remains unknown. Here, we show that KLF17 antagonizes ERα-dependent signaling to suppress breast cancer progression. KLF17 alters ERα-binding pattern throughout the genome and co-localizes with ERα on chromatin. Mechanistically, KLF17 forms a complex with ERα that interferes with ERα binding on chromatin and thereby attenuates ERα-dependent pathway. KLF17 increases the methylation status of ERE target promoters by recruiting transcriptional corepressor N-CoR/HDAC1 complex and prevents RNA polymerase II binding to suppress ERα-dependent transcriptional activation. Importantly, KLF17 preoccupies a subset of ERE target gene promoters and inhibits interaction of ERα with chromatin. Conversely, estrogen signaling suppresses KLF17 transcription via ERα/HDAC1-dependent mechanism. KLF17 expression negatively correlates with ERα target genes in multiple breast cancer samples. Enhanced KLF17 expression sensitizes ERα-positive breast cancer cells to endocrine therapy. KLF17 expression is downregulated in luminal breast cancer subtypes and is associated with poor survival rates in breast cancer patients. Taken together, these results indicate that KLF17-ERα interaction plays a potential role in inhibition of ERα-dependent breast cancer progression and suggests an improved strategy for treatment of ERα-positive breast cancer patients.

Tumor-suppressive p53 Signaling Empowers Metastatic Inhibitor KLF17-dependent Transcription to Overcome Tumorigenesis in Non-small Cell Lung Cancer.

Metastasis, which is controlled by concerted action of multiple genes, is a complex process and is an important cause of cancer death. Krüppel-like factor 17 (KLF17) is a negative regulator of metastasis and epithelial-mesenchymal transition (EMT) during cancer progression. However, the underlying molecular mechanism and biological relevance of KLF17 in cancer cells are poorly understood. Here, we show that tumor suppressor protein p53 plays an integral role to induce KLF17 expression in non-small cell lung cancer (NSCLC). p53 is recruited to the KLF17 promoter and results in the formation of p53-DNA complex. p53 enhances binding of p300 and favors histone acetylation on the KLF17 promoter. Mechanistically, p53 physically interacts with KLF17 and thereby enhances the anti-metastatic function of KLF17. p53 empowers KLF17-mediated EMT genes transcription via enhancing physical association of KLF17 with target gene promoters. Nutlin-3 recruits KLF17 to EMT target gene promoters and results in the formation of KLF17-DNA complex via a p53-dependent pathway. p53 depletion abrogates DNA binding affinity of KLF17 to EMT target gene promoters. KLF17 is critical for p53 cellular activities in NSCLC. Importantly, KLF17 enhances p53 transcription to generate a novel positive feedback loop. KLF17 depletion accelerates lung cancer cell growth in response to chemotherapy. Mechanistically, we found that KLF17 increases the expression of tumor suppressor genes p53, p21, and pRB. Functionally, KLF17 required p53 to suppress cancer cell invasion and migration in NSCLC. In conclusion, our study highlights a novel insight into the anti-EMT effect of KLF17 via a p53-dependent pathway in NSCLC, and KLF17 may be a new therapeutic target in NSCLC with p53 status.

CCl4 induced genotoxicity and DNA oxidative damages in rats: hepatoprotective effect of Sonchus arvensis.

BACKGROUND: Sonchus arvesis is traditionally reported in various human ailments including hepatotoxicity in Pakistan. Presently we designed to assess the protective effects of methanolic extract of Sonchus arvesis against carbon tetrachloride induced genotoxicity and DNA oxidative damages in hepatic tissues of experimental rats. METHODS: 36 male Sprague-Dawley rats were randomly divided into 6 groups to evaluate the hepatoprotective effects of Sonchus arvensis against CCl4 induced genotoxicity, DNA damages and antioxidant depletion. Rats of normal control group were given free access of food and water add labitum. Group II rats received 3 ml/kg of CCl4 (30% in olive oil v/v) via the intraperitoneal route twice a week for four weeks. Group III and IV received 1 ml of 100 mg/kg b.w. and 200 mg/kg b.w. SME via gavage after 48 h of CCl4 treatment whereas group V was given 1 ml of silymarin (100 mg/kg b.w.) after 48 h of CCl4 treatment. Group VI only received 200 mg/kg b.w. SME. Protective effects of SME were checked by measuring serum markers, activities of antioxidant enzymes, genotoxicity and DNA dmages. RESULTS: Results of the present study showed that treatment of SME reversed the activities of serum marker enzymes and cholesterol profile as depleted with CCl4 treatment. Activities of endogenous antioxidant enzymes of liver tissue homogenate; catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSHpx), glutathione-S-transferase (GST) and glutathione reductase (GSR) were reduced with administration of CCl4, which were returned to the control level with SME treatment. CCl4-induced hepatic cirrhosis decreased hepatic glutathione (GSH) and increased lipid peroxidative products (TBARS), were normalized by treatment with SME. Moreover, administration of CCl4 caused genotoxicity and DNA fragmentation which were significantly restored towards the normal level with SME. CONCLUSION: These results reveal that treatment of SME may be useful in the prevention of hepatic stress.

Molecular docking and in vitro studies of soap nut trypsin inhibitor (SNTI) against phospholipase A2 isoforms in therapeutic intervention of inflammatory diseases.

Therapeutic value of allelochemicals in inflammatory disorders and the potential drug targets need to be elucidated to alleviate tissue and vascular injury. Natural anti-inflammatory agents are known to cause minimal adverse effects. Presence of different secondary metabolites (allelochemicals), protease inhibitors like soap nut trypsin inhibitor (SNTI) from Sapindus trifoliatus and allied compounds from natural sources cannot be blithely ignored as natural therapeutics. In the present study, SNTI, a prospective protease inhibitor isolated from the seeds of Sapindus trifoliatus were subjected to docking against three isoforms of Phospholipase A2 (PLA2) molecules of the inflammatory pathways which are localized in the membrane, cytosol and pancreas. Eleven ligand molecules were selected from Sapindus trifoliatus and docked against membrane, cytosolic and pancreatic PLA2. Cytosolic PLA2 showed a strong inhibition by Kampferol, a secondary metabolite from seed endosperm of Sapindus trifoliatus. SNTI showed best interaction with membrane PLA2 in both in silico as well as in in vitro studies. SNTI showed IC50 value of 29.02 µM in in vitro assay. Docking interaction profiles and in vitro studies validate selected molecules from Sapindus trifoliatus as immunomodulators and can mollify inflammatory responses.

A Synopsis on the Role of Human Papilloma Virus Infection in Cervical Cancer.

BACKGROUND: Understanding of cervical cancer severity is still an important health issue across the world, especially for developing countries. Cancer or abnormal growth of the cell is one of the major health problems of the world. There are about two hundred types of malignancies reported till date. An updated statistic of all the main types of cancer and pathophysiology of cervical cancer is a significant need for designing the future treatment strategy. OBJECTIVE: In this review, a brief update on cancer, its causes and different types has been discussed along with updated statistics of patient's mortality. A brief overview of cervical cancer and its pathophysiology has been discussed with special emphasis on its causative agent, human papilloma virus (HPV). A brief introduction and update on genetics, molecular pathogenesis and prevalence of HPV and its role in cervical cancer have been added. CONCLUSION: This review delivered an updated status of cervical cancer and provide novel therapeutic approaches for targeting HPV. The detailed molecular and genomic information of the HPV help the researchers to develop more effective and efficacious therapeutic strategies and preventive vaccines that will significantly contribute to the control and anticipation of cervical cancer. Ultimately this may open new vistas to get rid of this deadly disease and may offer significant reduction in the numbers of advanced cervical cancers and deaths from cervical cancer in the affected nations.

Effect of Launaea procumbens extract on oxidative marker, p53, and CYP 2E1: a randomized control study.

BACKGROUND: Ethyl acetate extracts of Launaea procumbens is used for the treatment of liver dysfunction as an herbal medicine in Pakistan. In this study, the protective effects of ethyl acetate extracts were evaluated against CCl4-induced liver injuries in rat. METHODS: To examine the protective effects against oxidative stress of carbon tetrachloride in rats, 30 male rats were equally divided into 5 groups (6 rats). Among five groups, one was treated with CCl4 (3 ml/kg i.p. in olive oil b.w.) twice a week for 4 weeks. Others were orally fed with extracts (100, 200 mg/kg b.w.), with CCl4 twice a week for 4 weeks. RESULTS: Administration of CCl4 altered the serum marker enzymes, lipid profile, CYP 2E1, p53 expression, antioxidant enzymes, nuclear organizer regions (AgNORs), and DNA. Supplement of L. procumbens ameliorated the effects of CCl4, improved CYP 2E1, p53, and increased the activities of antioxidant enzymes while activity of liver marker enzymes (ALP, ALT, AST, g-GT) and contents of lipid per oxidation contents (TBARS), AgNORs, and DNA fragmentation were decreased. Similarly body weight was increased while liver and relative liver weight was decreased with co-administration of various extracts, suggesting that L. procumbens effectively protect liver against the CCl4-induced oxidative damage in rats. CONCLUSION: The hepatoprotective and free radical scavenging effects might be due to the presence of bioactive constituents in the extract.

Protective effects of Trifolium alexandrinum L. against lung injury induced by environmental toxin CCl4 in experimental rats.

BACKGROUND: In Pakistan numerous medicinal floras has used in the treatment of various human ailments. Among them Trifolium alexandrinum L. is traditionally used in the curing of disease. Presently we designed to ascertain the protective role of Trifolium alexandrinum methanolic extracts (TAME) against carbon tetrachloride (CCl4)-induced lung injury and oxidative stress in rats. METHODS: Exposure to CCl4 induces oxidative stress and causes tissue damage by the induction of CCl4 free radicals. Twenty-four male albino rats were divided equally into four groups. Rats in group I had free access to drinking water and laboratory food. Group II was treated with 1 ml/kg body weight (b.w.) CCl4 (30% in olive oil). Groups III and IV rats were fed (p.o.) 200 mg/kg b.w. TAME and 50 mg/kg b.w. silymarin after 24 h of CCl4 treatment for 2 weeks. RESULTS: Administration of CCl4 caused a significant (p<0.01) decrease in the activities of antioxidant enzymes (catalase, peroxidase, glutathione peroxidase, glutathione-S-transferase), and glutathione contents were decreased; however, thiobarbituric acid-reactive substances were increased (p<0.01). The alterations caused by CCl4 were significantly (p<0.01) reversed toward control levels by supplementation of TAME and silymarin. CONCLUSION: These results suggest that in rats TAME and silymarin could protect the lungs against CCl4-induced oxidative damage.

Protective effects of Carissa opaca fruits against CCl4-induced oxidative kidney lipid peroxidation and trauma in rat.

BACKGROUND: Carbon tetrachloride (CCl4) is a potent nephrotoxin, as it causes acute as well as chronic toxicity in kidneys. Therefore, this study was carried out to assess the pharmacological potential of different fractions of Carissa opaca fruits on CCl4-induced oxidative trauma in the kidney. METHODS: The parameters studied in this respect were the kidney function tests viz, serum profile, urine profile, genotoxicity, characteristic morphological findings, and antioxidant enzymatic level of kidneys. RESULT: The protective effects of various fractions of C. opaca fruits against CCl4 administration were reviewed by rat renal function alterations. Chronic toxicity caused by 8-week treatment of CCl4 to the rats significantly decreased the pH level, activities of antioxidant enzymes, and glutathione contents, whereas a significant increase was found in the case of specific gravity, red blood cells, white blood cells, level of urea, and lipid peroxidation in comparison to control group. Administration of various fractions of C. opaca fruit with CCl4 showed protective ability against CCl4 intoxication by restoring the urine profile, activities of antioxidant enzymes, and lipid peroxidation in rat. CCl4 induction in rats also caused DNA fragmentation and glomerular atrophy by means of dilation, disappearance of Bowmen's space, congestion in the capillary loops, dilation in renal tubules, and foamy look of epithelial cells of tubular region, which were restored by co-admiration of various fractions of C. opaca. CONCLUSION: Results revealed that the methanolic fractions of C. opaca are the most potent and helpful in kidney trauma.