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In the present study, we documented that doxorubicin (Dox) or cisplatin\u2010induced prostate cancer (PCa) chemoresistance is predominantly mediated by the induction of ABCG4 in androgen\u2010independent PCa cells. Treatment of DU\u2010145 or PC\u20103 cells with Dox significantly enhanced the expression of ABCG4 that resulted in the efflux of intracellular Dox. However, incubation of cells with ABCG4 short hairpin RNA resulted in a significant accumulation of Dox and sensitized cells to Dox\u2010induced cytotoxicity. Interestingly, simvastatin synergistically potentiated Dox\u2010induced cytotoxicity by inhibiting ABCG4 in DU\u2010145 and DU\u2010145 Dox<jats:sup>res<\/jats:sup> cells. Mechanistically, ABCG4 expression was regulated redox\u2010dependently by intracellular glutathione (GSH) levels. Treatment of cells with \n<jats:italic>N<\/jats:italic>\u2010acetylcysteine or simvastatin restored Dox\u2010induced depletion of GSH levels that in turn inhibited ABCG4 levels. In addition, a reduction in GSH levels by Dox caused a nuclear factor\u2010\u03baB dependent enhancement of c\u2010Myc expression, which led to cAMP\u2010regulatory element\u2010binding protein (CREB) activation. Furthermore, chromatin immunoprecipitation experiments revealed that Dox\u2010induced CREB activation transcriptionally upregulates ABCG4 expression. These results were further confirmed in an in vivo PCa xenograft mice model. Combination of simvastatin and Dox significantly regressed the tumor growth and size with no noticeable Dox\u2010induced cardiotoxic side effects. Intriguingly, DU\u2010145 cells with stably depleted ABCG4 levels not only significantly delayed the development of the tumor but also greatly sensitized the tumor to a low dose of Dox that resulted in complete tumor regression. Collectively, this data reinforces a novel function of ABCG4 in Dox\u2010mediated chemoresistance, and as a potential therapeutic target in drug\u2010induced PCa chemoresistance.<\/jats:p>","DOI":"10.1002\/mc.22996","type":"journal-article","created":{"date-parts":[[2019,3,5]],"date-time":"2019-03-05T05:05:01Z","timestamp":1551762301000},"page":"1118-1133","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Doxorubicin induces prostate cancer drug resistance by upregulation of ABCG4 through GSH depletion and CREB activation: Relevance of statins in chemosensitization"],"prefix":"10.1002","volume":"58","author":[{"given":"Sreevidya","family":"Mallappa","sequence":"first","affiliation":[{"name":"Centre for Chemical Biology CSIR\u2010Indian Institute of Chemical Technology Hyderabad India"},{"name":"Academy of Scientific and Innovative Research, Training and Development Complex Chennai 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