The role of mTOR inhibition in augmenting radiation induced autophagy.
Radiation affects both tumor and normal tissues, limiting the total delivered radiation dose. Therefore, novel ways to exploit molecular targets and improve the therapeutic ratio are continually being investigated. Autophagy plays an important role in cancer cell death decisions, particularly in solid tumors. This is counterbalanced by its function in cellular energy preservation. Recent studies have attempted to exploit autophagy in order to improve therapeutic ratio. However, direct inhibition of autophagy has been demonstrated to promote cancer cell death or survival dependent on cell type and condition. The mammalian target of rapamycin (mTOR) also regulates autophagy, as well as cell survival and proliferation pathways. Therefore, inhibition at this level of signaling would represent an excellent therapeutic target as it would limit cell growth, decrease cell proliferation, and boost autophagocytosis. Current investigations of mTOR inhibitors in combination with radiation appear to potentiate radiation's ability to induce autophagy. Further studies are necessary to fully elucidate which tumors have the most robust induction of autophagy in response to mTOR inhibition and radiation.
Jaboin
Jerry J
JJ
Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
Shinohara
Eric T
ET
Moretti
Luigi
L
Yang
Eddy S
ES
Kaminski
Joseph M
JM
Lu
Bo
B
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000187:drug effects* / Q000528:radiation effects*; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D009369:Neoplasms / Q000532:radiotherapy*; D011494:Protein Kinases / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases
D011838:Radiation-Sensitizing Agents; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus