4-hydroxy-tamoxifen induces autophagic death through K-Ras degradation

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 14; pp. 4395 - 4405
• Main Authors: Kohli, Latika, Kaza, Niroop, Coric, Tatjana, Byer, Stephanie J., Brossier, Nicole M., Klocke, Barbara J., Bjornsti, Mary-Ann, Carroll, Steven L., Roth, Kevin A.
• Format: Journal Article
• Language: English
• Published: 30-05-2013
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-3765

Tamoxifen is widely used to treat estrogen receptor (ER)-positive breast cancer. Recent findings that tamoxifen and its derivative 4-dehydroxy-tamoxifen (OHT) can exert ER-independent cytotoxic effects have prompted the initiation of clinical trials to evaluate its use in ER-negative malignancies. For example, tamoxifen and OHT exert cytotoxic effects in malignant peripheral nerve sheath tumors (MPNSTs) where estrogen is not involved. In this study, we gained insights into the ER-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 K-Ras degradation through autophagy induction, 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 tamoxifen and OHT in tumor cells that may be more broadly useful clinically in cancer treatment.