mTOR-targeted therapy: differential perturbation to mitochondrial membrane potential and permeability transition pore plays a role in therapeutic response.
Biochem Biophys Res Commun
; 447(1): 184-91, 2014 Apr 25.
Article
en En
| MEDLINE
| ID: mdl-24704448
While cancer cell mitochondria mediate actions of many successful chemotherapeutics, little is known about mitochondrial response in mTOR-targeted anticancer therapy. We have studied mitochondrial dynamics in relation to growth suppression employing an allosteric inhibitor rapalog, a highly selective mTOR kinase inhibitor (mTOR-KI) and mTOR-ShRNA. Global targeting of mTOR increased mitochondrial membrane potential (mΔψ) and inhibited mitochondrial permeability transition pore (mPTP). Importantly, these mTOR-KI-provoked anti-survival and pro-survival effects were differentially manifested in diverse cancer cells according to intrinsic susceptibility to mTOR-targeting. The most-sensitive cells including those possessing hyperactive PI3K/AKT/mTOR and/or growth factor-dependence (LNCap, MDA361 and MG63) all displayed a dramatic increase in mΔψ, whereas the mΔψ increase was not evident in majority of resistant cancer cells. Upon mTOR-KI treatment, the resistant cells including those harboring K-Ras- or B-Raf mutation (MDA231, HT29 and HCT116) all displayed a markedly reduced mPTP opening, which paralleled a sustained AKT-hexokinase 2 (HK2) survival signaling and persistent phosphorylation (inactivation) of GSK3ß. Further studies demonstrated that the mTOR-KI-provoked mPTP closure in resistant cells was mediated through an enhanced binding of HK2 to the mitochondrial voltage-dependent anion channel (VDAC), a molecular mechanism known to promote mPTP closure and cell survival. Detaching HK2 from VDAC by an HK2-displacing peptide or methyl jasmonate specifically blocked the mTOR-KI-provoked mPTP closure and potentiated growth suppression in resistant cells. Thus, mTOR-inhibition can exert complex and differential perturbation to mitochondrial dynamics in cancer cells, which likely influence therapeutic outcome of mTOR-targeted therapy.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas de Transporte de Membrana Mitocondrial
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Inhibidores de Proteínas Quinasas
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Potencial de la Membrana Mitocondrial
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Serina-Treonina Quinasas TOR
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Neoplasias
Límite:
Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos