Pharmacologic doses of ascorbic acid repress specificity protein (Sp) transcription factors and Sp-regulated genes in colon cancer cells Satya S. Pathi, Ping Lei, Sandeep Sreevalsan, Gayathri Chadalapaka, Indira Jutooru, Stephen Safe Nutrition and Cancer, 2011 Ascorbic acid (vitamin C) inhibits cancer cell growth, and there is a controversy regarding the cancer chemoprotective effects of pharmacologic doses of this compound that exhibits prooxidant activity. We hypothesized that the anticancer activity of pharmacologic doses of ascorbic acid (<5 mM) is due, in part, to reactive oxygen species-dependent downregulation of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 and Sp-regulated genes. In this study, ascorbic acid (1–3 mM) decreased RKO and SW480 colon cancer cell proliferation and induced apoptosis and necrosis, and this was accompanied by downregulation of Sp1, Sp3, and Sp4 proteins. In addition, ascorbic acid decreased expression of several Sp-regulated genes that are involved in cancer cell proliferation [hepatocyte growth factor receptor (c-Met), epidermal growth factor receptor and cyclin D1], survival (survivin and bcl-2), and angiogenesis [vascular endothelial growth factor (VEGF) and its receptors (VEGFR1 and VEGFR2)]. Other prooxidants such as hydrogen peroxide exhibited similar activities in colon cancer cells, and cotreatment with glutathione inhibited these responses. This study demonstrates for the first time that the anticancer activities of ascorbic acid are due, in part, to ROS-dependent repression of Sp transcription factors.
Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors Sudhakar Chintharlapalli, Sabitha Papineni, Ping Lei, Satya Pathi, Stephen Safe BMC Cancer, 2011 BackgroundBetulinic acid (BA) inhibits growth of several cancer cell lines and tumors and the effects of BA have been attributed to its mitochondriotoxicity and inhibition of multiple pro-oncogenic factors. Previous studies show that BA induces proteasome-dependent degradation of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 in prostate cancer cells and this study focused on the mechanism of action of BA in colon cancer cells.MethodsThe effects of BA on colon cancer cell proliferation and apoptosis and tumor growth in vivo were determined using standardized assays. The effects of BA on Sp proteins and Sp-regulated gene products were analyzed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a) and ZBTB10 mRNA expression.ResultsBA inhibited growth and induced apoptosis in RKO and SW480 colon cancer cells and inhibited tumor growth in athymic nude mice bearing RKO cells as xenograft. BA also decreased expression of Sp1, Sp3 and Sp4 transcription factors which are overexpressed in colon cancer cells and decreased levels of several Sp-regulated genes including survivin, vascular endothelial growth factor, p65 sub-unit of NFκB, epidermal growth factor receptor, cyclin D1, and pituitary tumor transforming gene-1. The mechanism of action of BA was dependent on cell context, since BA induced proteasome-dependent and proteasome-independent downregulation of Sp1, Sp3 and Sp4 in SW480 and RKO cells, respectively. In RKO cells, the mechanism of BA-induced repression of Sp1, Sp3 and Sp4 was due to induction of reactive oxygen species (ROS), ROS-mediated repression of microRNA-27a, and induction of the Sp repressor gene ZBTB10.ConclusionsThese results suggest that the anticancer activity of BA in colon cancer cells is due, in part, to downregulation of Sp1, Sp3 and Sp4 transcription factors; however, the mechanism of this response is cell context-dependent.
Inhibition of NFκB and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation Indira Jutooru, Gayathri Chadalapaka, Ping Lei, Stephen Safe Journal of Biological Chemistry, 2010 Curcumin activates diverse anticancer activities that lead to inhibition of cancer cell and tumor growth, induction of apoptosis, and antiangiogenic responses. In this study, we observed that curcumin inhibits Panc28 and L3.6pL pancreatic cancer cell and tumor growth in nude mice bearing L3.6pL cells as xenografts. In addition, curcumin decreased expression of p50 and p65 proteins and NFκB-dependent transactivation and also decreased Sp1, Sp3, and Sp4 transcription factors that are overexpressed in pancreatic cancer cells. Because both Sp transcription factors and NFκB regulate several common genes such as cyclin D1, survivin, and vascular endothelial growth factor that contribute to the cancer phenotype, we also investigated interactions between Sp and NFκB transcription factors. Results of Sp1, Sp3, and Sp4 knockdown by RNA interference demonstrate that both p50 and p65 are Sp-regulated genes and that inhibition of constitutive or tumor necrosis factor-induced NFκB by curcumin is dependent on down-regulation of Sp1, Sp3, and Sp4 proteins by this compound. Curcumin also decreased mitochondrial membrane potential and induced reactive oxygen species in pancreatic cancer cells, and this pathway is required for down-regulation of Sp proteins in these cells, demonstrating that the mitochondriotoxic effects of curcumin are important for its anticancer activities.
Peroxisome proliferator-activated receptor γ-dependent activity of indole ring-substituted 1,1-bis(3'-indolyl)-1-(p-biphenyl)methanes in cancer cells Jingjing Guo, Sudhakar Chintharlapalli, Syng-ook Lee, Sung Dae Cho, Ping Lei, Sabitha Papineni, Stephen Safe Cancer Chemotherapy and Pharmacology, 2010 Purpose1,1-Bis(3-indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) substituted in the phenyl ring with a para-, t-butyl, trifluoromethyl (DIM-C-pPhCF3) or phenyl (DIM-C-pPhC6H5) group activate peroxisome proliferator-activated receptor γ (PPARγ) in several cancer cell lines, and DIM-C-pPhCF3 also activates the orphan receptor Nur77. In this study, we have examined the effects of 5,5′-dihydroxy, 5,5′-dimethyl, 5,5′-dibromo, 5,5′-dinitro and 5,5′-dimethoxyindole ring-substituted analogs of DIM-C-pPhC6H5 on their activity as PPARγ agonists.MethodsVarious substituted C-DIM analogs were used to investigate their growth-inhibitory activities and activation of PPARγ-mediated transactivation in colon and pancreatic cancer cells. Their structure-dependent induction of putative PPARγ-responsive genes/proteins including p21, KLF-4 and caveolin1 were also determined by Western and Northern blot analysis.ResultsIntroduction of the 5,5′-dihydroxy and 5,5′-dimethyl substituents enhanced activation of PPARγ in colon and pancreatic cancer cells. However, activation of p21 in Panc28 pancreatic cancer cells and induction of caveolin-1 and KLF4 in colon cancer cells by the C-DIM compounds were structure- and cell context-dependent.ConclusionsThe results demonstrate that DIM-C-pPhC6H5 and indole ring-substituted analogs are selective PPARγ modulators.
Arsenic trioxide downregulates specificity protein (Sp) transcription factors and inhibits bladder cancer cell and tumor growth Indira Jutooru, Gayathri Chadalapaka, Sandeep Sreevalsan, Ping Lei, Rola Barhoumi, Robert Burghardt, Stephen Safe Experimental Cell Research, 2010 Arsenic trioxide exhibits antiproliferative, antiangiogenic and proapoptotic activity in cancer cells, and many genes associated with these responses are regulated by specificity protein (Sp) transcription factors. Treatment of cancer cells derived from urologic (bladder and prostate) and gastrointestinal (pancreas and colon) tumors with arsenic trioxide demonstrated that these cells exhibited differential responsiveness to the antiproliferative effects of this agent and this paralleled their differential repression of Sp1, Sp3 and Sp4 proteins in the same cell lines. Using arsenic trioxide-responsive KU7 and non-responsive 253JB-V bladder cancer cells as models, we show that in KU7 cells, < or =5 microM arsenic trioxide decreased Sp1, Sp3 and Sp4 and several Sp-dependent genes and responses including cyclin D1, epidermal growth factor receptor, bcl-2, survivin and vascular endothelial growth factor, whereas at concentrations up to 15 microM, minimal effects were observed in 253JB-V cells. Arsenic trioxide also inhibited tumor growth in athymic mice bearing KU7 cells as xenografts, and expression of Sp1, Sp3 and Sp4 was significantly decreased. Inhibitors of oxidative stress such as glutathione or dithiothreitol protected KU7 cells from arsenic trioxide-induced antiproliferative activity and Sp repression, whereas glutathione depletion sensitized 253JB-V cells to arsenic trioxide. Mechanistic studies suggested that arsenic trioxide-dependent downregulation of Sp and Sp-dependent genes was due to decreased mitochondrial membrane potential and induction of reactive oxygen species, and the role of peroxides in mediating these responses was confirmed using hydrogen peroxide.
The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy Shu Zhang, Ping Lei, Xinyi Liu, Xiangrong Li, Kelcey Walker, Leela Kotha, Craig Rowlands, Stephen Safe Endocrine Related Cancer, 2009 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the relatively non-toxic selective aryl hydrocarbon receptor (AhR) modulator 6-methyl-1,3,8-trichlorodibenzo-furan (MCDF) induced CYP1A1-dependent ethoxyresorufin O-deethylase activity and inhibited proliferation of seven estrogen receptor (ER) negative breast cancer cell lines. MCDF, TCDD and structurally related 2,3,7,8-tetrachlorodibenzofuran, 1,2,3,7,8-pentachlorodibenzo-p-dioxin, 2,3,4,7,8-pentachlorodibenzofuran, and 3,3′,4,4′,5-pentachlorobiphenyl induced CYP1A1 and inhibited proliferation of BT-474 and MDA-MB-468 cells. In BT474 and MDA-MB-468 cells transfected with a small inhibitory RNA for the AhR, the antiproliferative activity of the chlorinated aromatic compounds was reversed, whereas for MCDF, only partial reversal was observed, suggesting that this compound acts through both AhR-dependent and AhR-independent pathways in these two cell lines. MCDF also inhibited tumor growth in athymic nude mice in which MDA-MB-468 cells were injected directly into the mammary fat pad. These results suggest that the AhR is a potential drug target for treatment of ER-negative breast cancer.
The nonsteroidal anti-inflammatory drug tolfenamic acid inhibits BT474 and SKBR3 breast cancer cell and tumor growth by repressing erbB2 expression Xinyi Liu, Maen Abdelrahim, Ala Abudayyeh, Ping Lei, Stephen Safe Molecular Cancer Therapeutics, 2009 Tolfenamic acid (TA) is a nonsteroidal anti-inflammatory drug that inhibits pancreatic cancer cell and tumor growth through decreasing expression of specificity protein (Sp) transcription factors. TA also inhibits growth of erbB2-overexpressing BT474 and SKBR3 breast cancer cells; however, in contrast to pancreatic cancer cells, TA induced down-regulation of erbB2 but not Sp proteins. TA-induced erbB2 down-regulation was accompanied by decreased erbB2-dependent kinase activities, induction of p27, and decreased expression of cyclin D1. TA also decreased erbB2 mRNA expression and promoter activity, and this was due to decreased mRNA stability in BT474 cells and, in both cell lines, TA decreased expression of the YY1 and AP-2 transcription factors required for basal erbB2 expression. In addition, TA also inhibited tumor growth in athymic nude mice in which BT474 cells were injected into the mammary fat pad. TA represents a novel and promising new anticancer drug that targets erbB2 by decreasing transcription of this oncogene. [Mol Cancer Ther 2009;8(5):OF1–11]
Betulinic acid targets YY1 and ErbB2 through cannabinoid receptor-dependent disruption of microRNA-27a: ZBTB10 in breast cancer X Liu, I Jutooru, P Lei, KH Kim, S Lee, LK Brents, PL Prather, S Safe Molecular cancer therapeutics 11 (7), 1421-1431 , 2012 2012 Citations: 113
Pharmacologic doses of ascorbic acid repress specificity protein (Sp) transcription factors and Sp-regulated genes in colon cancer cells SS Pathi, P Lei, S Sreevalsan, G Chadalapaka, I Jutooru, S Safe Nutrition and cancer 63 (7), 1133-1142 , 2011 2011 Citations: 88
Inhibition of pituitary tumor‐transforming gene‐1 in thyroid cancer cells by drugs that decrease specificity proteins S Chintharlapalli, S Papineni, SO Lee, P Lei, UH Jin, SI Sherman, ... Molecular carcinogenesis 50 (9), 655-667 , 2011 2011 Citations: 57
Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and-independent downregulation of specificity proteins (Sp) transcription factors S Chintharlapalli, S Papineni, P Lei, S Pathi, S Safe BMC cancer 11 (1), 371 , 2011 2011 Citations: 209
Inhibition of NFκB and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation I Jutooru, G Chadalapaka, P Lei, S Safe Journal of Biological Chemistry 285 (33), 25332-25344 , 2010 2010 Citations: 248
Arsenic trioxide downregulates specificity protein (Sp) transcription factors and inhibits bladder cancer cell and tumor growth I Jutooru, G Chadalapaka, S Sreevalsan, P Lei, R Barhoumi, R Burghardt, ... Experimental cell research 316 (13), 2174-2188 , 2010 2010 Citations: 107
Peroxisome proliferator-activated receptor γ-dependent activity of indole ring-substituted 1,1-bis(3′-indolyl)-1-( p -biphenyl)methanes in cancer cells J Guo, S Chintharlapalli, S Lee, SD Cho, P Lei, S Papineni, S Safe Cancer chemotherapy and pharmacology 66 (1), 141-150 , 2010 2010 Citations: 27
The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy S Zhang, P Lei, X Liu, X Li, K Walker, L Kotha, C Rowlands, S Safe Endocrine-related cancer 16 (3), 835-844 , 2009 2009 Citations: 118
THE NSAID TOLFENAMIC ACID INHIBITS BT474 AND SKBR3 BREAST CANCER CELL AND TUMOR GROWTH BY REPRESSING erbB2 EXPRESSION X Liu, M Abdelrahim, S Abudayyeh, P Lei, S Safe Molecular cancer therapeutics 8 (5), 1207 , 2009 2009
The nonsteroidal anti-inflammatory drug tolfenamic acid inhibits BT474 and SKBR3 breast cancer cell and tumor growth by repressing erbB2 expression X Liu, M Abdelrahim, A Abudayyeh, P Lei, S Safe Molecular cancer therapeutics 8 (5), 1207-1217 , 2009 2009 Citations: 44
Structure-dependent activation of endoplasmic reticulum stress-mediated apoptosis in pancreatic cancer by 1, 1-bis (3′-indoly)-1-(p-substituted phenyl) methanes P Lei, M Abdelrahim, SD Cho, X Liu, S Safe Molecular cancer therapeutics 7 (10), 3363-3372 , 2008 2008 Citations: 49
Replication of the tumor necrosis factor receptor− associated factor 1/complement component 5 region as a susceptibility locus for rheumatoid arthritis in a European family … FAS Kurreeman, D Rocha, J Houwing‐Duistermaat, S Vrijmoet, ... Arthritis & Rheumatism 58 (9), 2670-2674 , 2008 2008 Citations: 36
5, 5′-Dibromo-bis (3′-indolyl) methane induces Kruppel-like factor 4 and p21 in colon cancer cells SD Cho, S Chintharlapalli, M Abdelrahim, S Papineni, S Liu, J Guo, P Lei, ... Molecular cancer therapeutics 7 (7), 2109-2120 , 2008 2008 Citations: 23
1,1- Bis (3′-indolyl)-1-( p -substituted phenyl)methanes inhibit colon cancer cell and tumor growth through activation of c-jun N-terminal … P Lei, M Abdelrahim, SD Cho, S Liu, S Chintharlapalli, S Safe Carcinogenesis 29 (6), 1139-1147 , 2008 2008 Citations: 59
1,1‐bis(3′‐indolyl)‐1‐( p ‐methoxyphenyl)methane activates Nur77‐independent proapoptotic responses in colon cancer cells SD Cho, P Lei, M Abdelrahim, K Yoon, S Liu, J Guo, S Papineni, ... Molecular Carcinogenesis: Published in cooperation with the University of … , 2008 2008 Citations: 34
Nur77 agonists induce proapoptotic genes and responses in colon cancer cells through nuclear receptor-dependent and independent pathways SD Cho, K Yoon, S Chintharlapalli, M Abdelrahim, P Lei, S Hamilton, ... Cancer Research 67 (9_Supplement), 5132-5132 , 2007 2007
Structure-dependent induction of endoplasmic reticulum stress and apoptosis in colon and pancreatic cancer cells by 1, 1-bis (3’-indolyl)-1-(p-substitutedphenyl) methanes P Lei, S Safe Cancer Research 67 (9_Supplement), 1456-1456 , 2007 2007
Nur77 agonists induce proapoptotic genes and responses in colon cancer cells through nuclear receptor–dependent and nuclear receptor–independent pathways SD Cho, K Yoon, S Chintharlapalli, M Abdelrahim, P Lei, S Hamilton, ... Cancer research 67 (2), 674-683 , 2007 2007 Citations: 203
1,1-Bis(3′-indolyl)-1-( p -substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator–activated receptor–dependent and … P Lei, M Abdelrahim, S Safe Molecular cancer therapeutics 5 (9), 2324-2336 , 2006 2006 Citations: 43
1, 1-Bis (3'-indolyl)-1-(p-tbutylphenyl) methane inhibits ovarian cancer cell growth through PPAR gamma-dependent and-independent pathways P Lei, M Abdelrahim, S Safe CANCER RESEARCH 66 (8) , 2006 2006
MOST CITED SCHOLAR PUBLICATIONS
Inhibition of NFκB and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation I Jutooru, G Chadalapaka, P Lei, S Safe Journal of Biological Chemistry 285 (33), 25332-25344 , 2010 2010 Citations: 248
Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and-independent downregulation of specificity proteins (Sp) transcription factors S Chintharlapalli, S Papineni, P Lei, S Pathi, S Safe BMC cancer 11 (1), 371 , 2011 2011 Citations: 209
Nur77 agonists induce proapoptotic genes and responses in colon cancer cells through nuclear receptor–dependent and nuclear receptor–independent pathways SD Cho, K Yoon, S Chintharlapalli, M Abdelrahim, P Lei, S Hamilton, ... Cancer research 67 (2), 674-683 , 2007 2007 Citations: 203
The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy S Zhang, P Lei, X Liu, X Li, K Walker, L Kotha, C Rowlands, S Safe Endocrine-related cancer 16 (3), 835-844 , 2009 2009 Citations: 118
Betulinic acid targets YY1 and ErbB2 through cannabinoid receptor-dependent disruption of microRNA-27a: ZBTB10 in breast cancer X Liu, I Jutooru, P Lei, KH Kim, S Lee, LK Brents, PL Prather, S Safe Molecular cancer therapeutics 11 (7), 1421-1431 , 2012 2012 Citations: 113
Arsenic trioxide downregulates specificity protein (Sp) transcription factors and inhibits bladder cancer cell and tumor growth I Jutooru, G Chadalapaka, S Sreevalsan, P Lei, R Barhoumi, R Burghardt, ... Experimental cell research 316 (13), 2174-2188 , 2010 2010 Citations: 107
Pharmacologic doses of ascorbic acid repress specificity protein (Sp) transcription factors and Sp-regulated genes in colon cancer cells SS Pathi, P Lei, S Sreevalsan, G Chadalapaka, I Jutooru, S Safe Nutrition and cancer 63 (7), 1133-1142 , 2011 2011 Citations: 88
1,1- Bis (3′-indolyl)-1-( p -substituted phenyl)methanes inhibit colon cancer cell and tumor growth through activation of c-jun N-terminal … P Lei, M Abdelrahim, SD Cho, S Liu, S Chintharlapalli, S Safe Carcinogenesis 29 (6), 1139-1147 , 2008 2008 Citations: 59
Inhibition of pituitary tumor‐transforming gene‐1 in thyroid cancer cells by drugs that decrease specificity proteins S Chintharlapalli, S Papineni, SO Lee, P Lei, UH Jin, SI Sherman, ... Molecular carcinogenesis 50 (9), 655-667 , 2011 2011 Citations: 57
Structure-dependent activation of endoplasmic reticulum stress-mediated apoptosis in pancreatic cancer by 1, 1-bis (3′-indoly)-1-(p-substituted phenyl) methanes P Lei, M Abdelrahim, SD Cho, X Liu, S Safe Molecular cancer therapeutics 7 (10), 3363-3372 , 2008 2008 Citations: 49
The nonsteroidal anti-inflammatory drug tolfenamic acid inhibits BT474 and SKBR3 breast cancer cell and tumor growth by repressing erbB2 expression X Liu, M Abdelrahim, A Abudayyeh, P Lei, S Safe Molecular cancer therapeutics 8 (5), 1207-1217 , 2009 2009 Citations: 44
1,1-Bis(3′-indolyl)-1-( p -substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator–activated receptor–dependent and … P Lei, M Abdelrahim, S Safe Molecular cancer therapeutics 5 (9), 2324-2336 , 2006 2006 Citations: 43
Replication of the tumor necrosis factor receptor− associated factor 1/complement component 5 region as a susceptibility locus for rheumatoid arthritis in a European family … FAS Kurreeman, D Rocha, J Houwing‐Duistermaat, S Vrijmoet, ... Arthritis & Rheumatism 58 (9), 2670-2674 , 2008 2008 Citations: 36
1,1‐bis(3′‐indolyl)‐1‐( p ‐methoxyphenyl)methane activates Nur77‐independent proapoptotic responses in colon cancer cells SD Cho, P Lei, M Abdelrahim, K Yoon, S Liu, J Guo, S Papineni, ... Molecular Carcinogenesis: Published in cooperation with the University of … , 2008 2008 Citations: 34
Peroxisome proliferator-activated receptor γ-dependent activity of indole ring-substituted 1,1-bis(3′-indolyl)-1-( p -biphenyl)methanes in cancer cells J Guo, S Chintharlapalli, S Lee, SD Cho, P Lei, S Papineni, S Safe Cancer chemotherapy and pharmacology 66 (1), 141-150 , 2010 2010 Citations: 27
5, 5′-Dibromo-bis (3′-indolyl) methane induces Kruppel-like factor 4 and p21 in colon cancer cells SD Cho, S Chintharlapalli, M Abdelrahim, S Papineni, S Liu, J Guo, P Lei, ... Molecular cancer therapeutics 7 (7), 2109-2120 , 2008 2008 Citations: 23
THE NSAID TOLFENAMIC ACID INHIBITS BT474 AND SKBR3 BREAST CANCER CELL AND TUMOR GROWTH BY REPRESSING erbB2 EXPRESSION X Liu, M Abdelrahim, S Abudayyeh, P Lei, S Safe Molecular cancer therapeutics 8 (5), 1207 , 2009 2009
Nur77 agonists induce proapoptotic genes and responses in colon cancer cells through nuclear receptor-dependent and independent pathways SD Cho, K Yoon, S Chintharlapalli, M Abdelrahim, P Lei, S Hamilton, ... Cancer Research 67 (9_Supplement), 5132-5132 , 2007 2007
Structure-dependent induction of endoplasmic reticulum stress and apoptosis in colon and pancreatic cancer cells by 1, 1-bis (3’-indolyl)-1-(p-substitutedphenyl) methanes P Lei, S Safe Cancer Research 67 (9_Supplement), 1456-1456 , 2007 2007
1, 1-Bis (3'-indolyl)-1-(p-tbutylphenyl) methane inhibits ovarian cancer cell growth through PPAR gamma-dependent and-independent pathways P Lei, M Abdelrahim, S Safe CANCER RESEARCH 66 (8) , 2006 2006
