Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells.
Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) is a lipid phosphatase with putative tumor suppressing abilities, which is frequently mutated in prostate cancer. Loss of PTEN leads to constitutive activation of the phosphatidylinositol 3'-kinase/serine-threonine kinase (Akt) signal transduction pathway and has been associated with resistance to chemotherapy. This study aimed to determine the effects of PTEN status and treatment with rapamycin, an inhibitor of mTOR, in the response of prostate cancer cell lines to doxorubicin. The DU-145 PTEN-positive cell line was significantly more susceptible to the antiproliferative effects of doxorubicin as compared with the PTEN-negative PC-3 cell line. Transfection of PTEN into the PC3 cells decreased the activation of Akt and the downstream mTOR-regulated 70-kDa S6 (p70(s6k)) kinase and reversed the resistance to doxorubicin in these cells, indicating that changes in PTEN status/Akt activation modulate the cellular response to doxorubicin. Treatment of PC-3 PTEN-negative cells with rapamycin inhibited 70-kDa S6 kinase and increased the proliferative response of these cells to doxorubicin, so that it was comparable with the responses of PTEN-positive DU-145 cells and the PC-3-transfected cells. Furthermore, treatment of mice bearing the PTEN-negative PC-3 prostate cancer xenografts with CCI-779, an ester of rapamycin in clinical development combined with doxorubicin, inhibited the growth of the doxorubicin-resistant PC-3 tumors confirming the observations in vitro. Thus, rapamycin and CCI-779, by interacting with downstream intermediates in the phosphatidylinositol 3'-kinase/Akt signaling pathway, reverse the resistance to doxorubicin conferred by PTEN mutation/Akt activation. These results provide the rationale to explore in clinical trials whether these agents increase the response to chemotherapy of patients with PTEN-negative/Akt active cancers.
Grünwald
Viktor
V
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
DeGraffenried
Linda
L
Russel
Douglas
D
Friedrichs
William E
WE
Ray
Ratna B
RB
Hidalgo
Manuel
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020123:Sirolimus