Colorectal cancer is one of the leading causes of death in most developed countries including the United States. Colon cancer chemotherapy relies on a number of cytotoxic drugs, targeted agents and their combinations, and there is an increasing need to develop alternative drugs targeting specific pathways that inhibit tumor growth, progression and metastasis and induce apoptosis. Specificity proteins (Sps) are transcription factors overexpressed in many tumors, and Sps regulate expression of genes required for cancer cell and tumor growth (p27 suppression), survival (survivin), and angiogenesis (VEGF, VEGFR1 and VEGFR2). Studies in this laboratory have now shown that tolfenamic acid (TA) and betulinic acid (BA) and a novel synthetic triterpenoid acid (ester), namely methyl-2-cyano-3,11-dioxo-18?-olean-1,12-dien-30-oate (CDODA-Me) induce G2/M growth arrest and proteasome-independent degradation of Sp proteins in colon cancer cells. These effects are directly linked to compound-induced modulation of expression of oncogenic microRNA-27a (mir-27a) and other miRs. Therefore, we hypothesize that TA, BA and CDODA-Me represent a unique class of anticancer agents that target miR-27a and other miRs. The proposed studies will characterize the mechanisms of action and effects resulting from drug-miR interactions in colon cancer.
Aim 1 will focus on TA-/BA-/CDODA-Me-miR-27a interactions and investigate the activation of miR-27a-dependent ZBTB10 and Myt-1 expression and their subsequent downstream modulation of Sp and Sp-dependent genes, growth inhibitory, antiangiogenic and proapoptotic responses in colon cancer cells. TA, BA and CDODA-Me also decrease expression of other miRs in colon cancer cells, and these include miR-23a and miR-24-2 which form a cluster with miR-27a.
Aim 2 will investigate TA-, BA- and CDODA-Me-miR(23a~24-2) interactions and determine their role in mediating the anticarcinogenic activities of these compounds.
Aim 3 will investigate the in vivo anticarcinogenic activity of TA, BA and CDODA-Me in a mouse xenograft and "Min" model for colon cancer and determine the compound-miR interactions. In addition, mice overexpressing miR-27a have been developed as probes for investigating the role of this oncogenic miR in colon carcinogenesis. These studies will provide critical data on the efficacy and mechanisms of action of TA, BA and CDODA-Me as a novel class of anticancer drugs that act through multiple pathways including direct effects on microRNAs and their associated gene transcripts.

Public Health Relevance

Recent studies in this laboratory have identified two structural classes of compounds that induce Sp protein repression in cancers and inhibit cancer cell growth and survival. These compounds include the triterpenoids betulinic acid (BA) and methyl 2-cyano-3,11-dioxo-18?-olean-1,12-dien-30-oate (CDODA-Me) and the NSAID tolfenamic acid (TA). The studies proposed in this project will focus on the mechanisms of action of these anticancer agents with emphasis on their effects on the oncogenic microRNA-27a (miR-27a) and other miRs and the role in repression of Sp proteins and other critical genes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136571-04
Application #
8260227
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
2009-06-03
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$259,757
Indirect Cost
$78,609
Name
Texas A&M University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
078592789
City
College Station
State
TX
Country
United States
Zip Code
77845
Pathi, Satya; Li, Xi; Safe, Stephen (2014) Tolfenamic acid inhibits colon cancer cell and tumor growth and induces degradation of specificity protein (Sp) transcription factors. Mol Carcinog 53 Suppl 1:E53-61
Nair, Vijayalekshmi; Sreevalsan, Sandeep; Basha, Riyaz et al. (2014) Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: role of specificity protein (Sp) transcription factors. J Biol Chem 289:27692-701
Yang, Won Seok; Chadalapaka, Gayathri; Cho, Sung-Gook et al. (2014) The transcriptional repressor ZBTB4 regulates EZH2 through a MicroRNA-ZBTB4-specificity protein signaling axis. Neoplasia 16:1059-69
Sreevalsan, Sandeep; Safe, Stephen (2013) The cannabinoid WIN 55,212-2 decreases specificity protein transcription factors and the oncogenic cap protein eIF4E in colon cancer cells. Mol Cancer Ther 12:2483-93
Nair, Vijayalekshmi; Pathi, Satya; Jutooru, Indira et al. (2013) Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors. Carcinogenesis 34:2870-9
Chadalapaka, Gayathri; Jutooru, Indira; Sreevalsan, Sandeep et al. (2013) Inhibition of rhabdomyosarcoma cell and tumor growth by targeting specificity protein (Sp) transcription factors. Int J Cancer 132:795-806
Sreevalsan, Sandeep; Safe, Stephen (2013) REACTIVE OXYGEN SPECIES AND COLORECTAL CANCER. Curr Colorectal Cancer Rep 9:350-357
Gandhy, Shruti U; Kim, Kyounghyun; Larsen, Lesley et al. (2012) Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp) transcription factors by targeting microRNAs. BMC Cancer 12:564
Kim, K; Chadalapaka, G; Lee, S-O et al. (2012) Identification of oncogenic microRNA-17-92/ZBTB4/specificity protein axis in breast cancer. Oncogene 31:1034-44
Liu, Xinyi; Jutooru, Indira; Lei, Ping et al. (2012) Betulinic acid targets YY1 and ErbB2 through cannabinoid receptor-dependent disruption of microRNA-27a:ZBTB10 in breast cancer. Mol Cancer Ther 11:1421-31

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