Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Anticancer drugs induce tumor drug-resistance and metastasis, and cancer stem cells display more resistant than other differentied cancer cells;however, little is known whether anticancer drugs promote cancer stem cells. The goal of this project is to determine the role of ceramide glycosylation in mediating cancer stem cells during the course of chemotherapy. To complet the goal, we pursued two specific aims in last year: 1), determine the increasements of glucosylceramide synthase (GCS) and breast cancer stem cell (BCSC) in drug-resistant cancer cells;2), identify the induction of doxorubicin in cancer stem cells via ceramide glycosylation in vivo. We found that GCS overexpression was interrelated to the increment BCSCs and drug-resistance in human breast cancer MCF-7 cell lines after doxorubicin induction. With GCS overexpression, the BCSCs of CD24-/CD44+/ESA+ phenotype was increased by 5-fold in MCF-7/Dox cells as compared to MCF-7 cells. Silencing GCS by using mixed-backbone oligonucleotide (MBO-asGCS) significantly decreased the numbers of BCSCs more than 2-fold. BCSCs sorted displayed 3-fold higher GCS enzyme activity and formed 2-fold more colonies, as compare with other non-stem cell subsets. The BCSCs cells showed significantly higher tumorigenicity and metastasibility as compared to non-stem cells in athymic nude mice. More interestingly, doxorubicin treatment considerably increased BCSCs by 2-fold in tumors, and MBO-asGCS treatment eliminated the tumor growth and reduced metastasis due to reduction of BCSCs. Comparison of glycosphingolipids and gene profile indicated GCS or globo-series glycosphingolipids regulates FGF1 and others to accumulate BCSCs. These results demonstrate that ceramide glycosylation accumulates BCSCs formation and causes aggressive tumor progression.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR016456-10
Application #
8360364
Study Section
Special Emphasis Panel (ZRR1-RI-7 (01))
Project Start
2011-05-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
10
Fiscal Year
2011
Total Cost
$164,824
Indirect Cost

  Institution

Name
Louisiana State University A&M Col Baton Rouge
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
075050765
City
Baton Rouge
State
LA
Country
United States
Zip Code
70803

  Publications

Hosain, Salman B; Khiste, Sachin K; Uddin, Mohammad B et al. (2016) Inhibition of glucosylceramide synthase eliminates the oncogenic function of p53 R273H mutant in the epithelial-mesenchymal transition and induced pluripotency of colon cancer cells. Oncotarget 7:60575-60592
Pogue, A I; Dua, P; Hill, J M et al. (2015) Progressive inflammatory pathology in the retina of aluminum-fed 5xFAD transgenic mice. J Inorg Biochem 152:206-9
Zhang, Cheng; Rissman, Robert A; Feng, June (2015) Characterization of ATP alternations in an Alzheimer's disease transgenic mouse model. J Alzheimers Dis 44:375-8
Gu, Ying; Barzegar, Mansoureh; Chen, Xin et al. (2015) Fusarochromanone-induced reactive oxygen species results in activation of JNK cascade and cell death by inhibiting protein phosphatases 2A and 5. Oncotarget 6:42322-33
Pasluosta, Cristian F; Chiu, Alan W L (2015) Modulation of grasping force in prosthetic hands using neural network-based predictive control. Methods Mol Biol 1260:179-94
Ibrahim, Sulaimon; Chowriappa, Pradeep; Dua, Sumeet et al. (2015) Classification of diabetes maculopathy images using data-adaptive neuro-fuzzy inference classifier. Med Biol Eng Comput 53:1345-60
Babu, Sainath; Uppu, Sannihith N; Martin, Brittany et al. (2015) Unusually high levels of bisphenol A (BPA) in thermal paper cash register receipts (CRs): development and application of a robust LC-UV method to quantify BPA in CRs. Toxicol Mech Methods 25:410-6
El-Saadi, Madison Wynne; Williams-Hart, Tara; Salvatore, Brian A et al. (2015) Use of in-silico assays to characterize the ADMET profile and identify potential therapeutic targets of fusarochromanone, a novel anti-cancer agent. In Silico Pharmacol 3:6
Kheterpal, Indu; Scherp, Peter; Kelley, Lauren et al. (2014) Bioactives from Artemisia dracunculus L. enhance insulin sensitivity via modulation of skeletal muscle protein phosphorylation. Nutrition 30:S43-51
El Hajj, Elia C; El Hajj, Milad C; Voloshenyuk, Tetyana G et al. (2014) Alcohol modulation of cardiac matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs favors collagen accumulation. Alcohol Clin Exp Res 38:448-56

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