Guggulsterone and bexarotene induce secretion of exosome-associated breast cancer resistance protein and reduce doxorubicin resistance in MDA-MB-231 cells.

Abstract

Many breast cancer cells acquire multidrug resistance (MDR) mediated by ABC transporters such as breast cancer resistance protein (BCRP/ABCG2). Here we show that incubation of human breast cancer MDA-MB-231 cells with farnesoid X receptor antagonist guggulsterone (gug) and retinoid X receptor agonist bexarotene (bex) elevated ceramide, a sphingolipid known to induce exosome secretion. The gug+bex combination reduced cellular levels of BCRP to 20% of control cells by inducing its association and secretion with exosomes. Exogenous C6 ceramide also induced secretion of BCRP-associated exosomes, while siRNA-mediated knockdown or GW4869-mediated inhibition of neutral sphingomyelinase 2 (nSMase2), an enzyme generating ceramide, restored cellular BCRP. Immunocytochemistry showed that ceramide elevation and concurrent loss of cellular BCRP was prominent in Aldefluor-labeled breast cancer stem-like cells. These cells no longer excluded the BCRP substrate Hoechst 33342 and showed caspase activation and apoptosis induction. Consistent with reduced BCRP, ABC transporter assays showed that gug+bex increased doxorubicin retention and that the combination of gug+bex with doxorubicin enhanced cell death by more than fivefold. Taken together, our results suggest a novel mechanism by which ceramide induces BCRP secretion and reduces MDR, which may be useful as adjuvant drug treatment for sensitizing breast cancer cells and cancer stem cells to chemotherapy.

• Authors: Ji Na Kong, Qian He, Guanghu Wang, Somsankar Dasgupta, Michael B Dinkins, Gu Zhu, Austin Kim, Stefka Spassieva, Erhard Bieberich
• Journal: International journal of cancer (Int J Cancer) Vol. 137 Issue 7 Pg. 1610-20 (Oct 01 2015) ISSN: 1097-0215 [Electronic] United States
• PMID: 25833198 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2015 UICC.

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Ceramides
• Neoplasm Proteins
• Pregnenediones
• Tetrahydronaphthalenes
• Doxorubicin
• pregna-4,17-diene-3,16-dione
• Bexarotene

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (metabolism)
• Bexarotene
• Breast Neoplasms (drug therapy, pathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Ceramides (biosynthesis)
• Down-Regulation (drug effects)
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm
• Drug Synergism
• Exosomes (drug effects, metabolism)
• Humans
• Neoplasm Proteins (metabolism)
• Pregnenediones (pharmacology)
• Tetrahydronaphthalenes (pharmacology)