Cancer cells with defective RB and CDKN2A are resistant to the apoptotic effects of rapamycin.

Autor: Chakraborty S; Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA; Biochemistry Program, Graduate Center of the City University of New York, NY, New York, USA., Utter MB; Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA; Biochemistry Program, Graduate Center of the City University of New York, NY, New York, USA., Frias MA; Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA., Foster DA; Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA; Biochemistry Program, Graduate Center of the City University of New York, NY, New York, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. Electronic address: foster@genectr.hunter.cuny.edu.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2021 Dec 01; Vol. 522, pp. 164-170. Date of Electronic Publication: 2021 Sep 23.
DOI: 10.1016/j.canlet.2021.09.020
Abstrakt: Inhibition of mammalian target of rapamycin complex 1 (mTORC1) with rapamycin in the absence of transforming growth factor-β (TGFβ) signaling induces apoptosis in many cancer cell lines. In the presence of TGFβ, rapamycin induces G 1 cell cycle arrest; however, in the absence of TGFβ, cells do not arrest in G 1 and progress into S-phase where rapamycin is cytotoxic rather than cytostatic. However, we observed that DU145 prostate and NCI-H2228 lung cancer cells were resistant to the cytotoxic effect of rapamycin. Of interest, the rapamycin-resistant DU145 and NCI-H2228 cells have mutations in the RB and CDKN2A tumor suppressor genes. The gene products of RB and CDKN2A (pRb and p14 ARF ) suppress E2F family transcription factors that promote cell cycle progression from G 1 into S. Restoration of wild type RB or inhibition of E2F activity in DU145 and NCI-H2228 cells led to rapamycin sensitivity. These data provide evidence that the combination of mutant RB and mutant CDKN2A in cancer cells leads to rapamycin resistance, which has implications for precision medicine approaches to anti-cancer therapies.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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