Regulation of D-cyclin translation inhibition in myeloma cells treated with mammalian target of rapamycin inhibitors: rationale for combined treatment with extracellular signal-regulated kinase inhibitors and rapamycin.

Molecular Cancer Therapeutics
Patrick FrostAlan Lichtenstein

Abstract

We have shown that heightened AKT activity sensitized multiple myeloma cells to the antitumor effects of the mammalian target of rapamycin inhibitor CCI-779. To test the mechanism of the AKT regulatory role, we stably transfected U266 multiple myeloma cell lines with an activated AKT allele or empty vector. The AKT-transfected cells were more sensitive to cytostasis induced in vitro by rapamycin or in vivo by its analogue, CCI-779, whereas cells with quiescent AKT were resistant. The ability of mammalian target of rapamycin inhibitors to down-regulate D-cyclin expression was significantly greater in AKT-transfected multiple myeloma cells due, in part, to the ability of AKT to curtail cap-independent translation and internal ribosome entry site (IRES) activity of D-cyclin transcripts. Similar AKT-dependent regulation of rapamycin responsiveness was shown in a second myeloma model: the PTEN-null OPM-2 cell line transfected with wild-type PTEN. Because extracellular signal-regulated kinase (ERK)/p38 activity facilitates IRES-mediated translation of some transcripts, we investigated ERK/p38 as regulators of AKT-dependent effects on rapamycin sensitivity. AKT-transfected U266 cells showed significantly decreased ERK and p38 activity...Continue Reading

References

Nov 1, 1995·British Journal of Haematology·N Juge-MorineauR Bataille
Jun 11, 1998·The Journal of Biological Chemistry·S HashemolhosseiniS Ferrari
Sep 15, 1999·Proceedings of the National Academy of Sciences of the United States of America·Q ZongD R Morris
Nov 27, 1999·Science·S Zimmermann, K Moelling
Jan 29, 2000·Molecular and Cellular Biology·M StoneleyA E Willis
Mar 9, 2000·Annals of Oncology : Official Journal of the European Society for Medical Oncology·M ChesiP L Bergsagel
Aug 16, 2001·Proceedings of the National Academy of Sciences of the United States of America·M S NeshatC L Sawyers
Oct 25, 2001·Blood·J HsuA Lichtenstein
Jul 3, 2002·Human Pathology·Masahiro SugawaraBryan R Haugen
Dec 5, 2002·Genes & Development·Michael KullmannLudger Hengst
Jul 25, 2003·Cancer Biology & Therapy·Shile HuangPeter J Houghton
Apr 9, 2004·Blood·Thomas StrömbergHelena Jernberg-Wiklund

❮ Previous
Next ❯

Citations

Feb 15, 2011·Cell Division·Woan-Yuh Tarn, Ming-Chih Lai
Sep 15, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Sonali M SmithBarbara Pro
Jun 3, 2011·The Oncologist·Anas Younes, Nousheen Samad
May 24, 2011·Leukemia & Lymphoma·Joseph Gera, Alan Lichtenstein
Jun 7, 2013·Expert Opinion on Biological Therapy·Gabriella MissoMichele Caraglia
Jan 7, 2016·Frontiers in Oncology·Emilie HorvilleurAnne E Willis
Apr 28, 2009·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Paul DentSteven Grant
Dec 3, 2013·International Journal of Cancer. Journal International Du Cancer·Maria Beatrice MorelliMassimo Nabissi
Aug 6, 2010·Blood·Bao HoangAlan Lichtenstein
Jul 14, 2019·The Journal of Pathology·Hoin KangWook Kim
Jul 21, 2020·RNA Biology·Gunhild Sommer, Tilman Heise
Oct 3, 2017·Bone Marrow Transplantation·P A Riedell, M R Bishop
Jan 24, 2016·Molecular Cancer Research : MCR·Veena S MysorePatrick J Frost

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.