mTOR-targeted therapy: differential perturbation to mitochondrial membrane potential and permeability transition pore plays a role in therapeutic response.
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 GSK3β. 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.
Oncology Research, Pfizer Pharmaceuticals, Pearl River, NY 10965, USA.
Jae Eun
JE
Kim
Department of Pharmacology, Fudan University, School of Pharmacy, Shanghai 201203, China.
Qun
Q
He
Department of Pharmacology, Fudan University, School of Pharmacy, Shanghai 201203, China.
Yaqing
Y
Chen
Oncology Research, Pfizer Pharmaceuticals, Pearl River, NY 10965, USA.
Celine
C
Shi
Department of Pharmacology, Fudan University, School of Pharmacy, Shanghai 201203, China; Oncology Research, Pfizer Pharmaceuticals, Pearl River, NY 10965, USA. Electronic address: keryu@fudan.edu.cn.
Ker
K
Yu
D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D009369:Neoplasms / Q000188:drug therapy*; D010671:Phenylurea Compounds / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D050995:Voltage-Dependent Anion Channel 1 / Q000187:drug effects
D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D058570:TOR Serine-Threonine Kinases; D050995:Voltage-Dependent Anion Channel 1; C547581:WYE 125132; C546842:MTOR protein, human; C000605506:GSK3B protein, human
Anticancer; Mitochondria; mTOR inhibitor