title: 4-Hydroxytamoxifen induces autophagic death through K-Ras degradation.
abstract: Tamoxifen is widely used to treat estrogen receptor-positive breast cancer. Recent findings that tamoxifen and its derivative 4-hydroxytamoxifen (OHT) can exert estrogen receptor-independent cytotoxic effects have prompted the initiation of clinical trials to evaluate its use in estrogen receptor-negative malignancies. For example, tamoxifen and OHT exert cytotoxic effects in malignant peripheral nerve sheath tumors (MPNST) where estrogen is not involved. In this study, we gained insights into the estrogen receptor-independent cytotoxic effects of OHT by studying how it kills MPNST cells. Although caspases were activated following OHT treatment, caspase inhibition provided no protection from OHT-induced death. Rather, OHT-induced death in MPNST cells was associated with autophagic induction and attenuated by genetic inhibition of autophagic vacuole formation. Mechanistic investigations revealed that OHT stimulated autophagic degradation of K-Ras, which is critical for survival of MPNST cells. Similarly, we found that OHT induced K-Ras degradation in breast, colon, glioma, and pancreatic cancer cells. Our findings describe a novel mechanism of autophagic death triggered by OHT in tumor cells that may be more broadly useful clinically in cancer treatment.
authors.affiliation: Departments of Pathology, Cell Biology, and Pharmacology and Toxicology, and Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Latika
authors.initials: L
authors.lastname: Kohli
authors.forename: Niroop
authors.initials: N
authors.lastname: Kaza
authors.forename: Tatjana
authors.initials: T
authors.lastname: Coric
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Byer
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Brossier
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Klocke
authors.forename: Mary-Ann
authors.initials: MA
authors.lastname: Bjornsti
authors.forename: Steven L
authors.initials: SL
authors.lastname: Carroll
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Roth
mesh_terms: D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene; C512478:EGFR protein, human; D066246:ErbB Receptors; D011493:Protein Kinase C; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins