Inhibition of Mammalian Target of Rapamycin or Apoptotic Pathway Induces Autophagy and Radiosensitizes PTEN Null Prostate Cancer Cells

Abstract

The phosphatidylinositol 3-kinase/Akt pathway plays a critical role in oncogenesis, and dysregulation of this pathway through loss of PTEN suppression is a particularly common phenomenon in aggressive prostate cancers. The mammalian target of rapamycin (mTOR) is a downstream signaling kinase in this pathway, exerting prosurvival influence on cells through the activation of factors involved in protein synthesis.

Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma

“…16,44 Moreover, rapamycin, which induces autophagy by inhibiting the mTOR kinase, has been demonstrated to be a potent therapeutic strategy for many tumor types in clinical studies. 45 We also found SAHA induced autophagy through inhibition of mTOR activity. Consistently, suppression of the early stage by 3-MA or Atg5 knockout reduced SAHA-induced cytotoxicity.…”

Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells

“…These findings are consistent with those showing that disabled apoptosis results in increased radiosensitivity in MCF-7 cells, 25 Bax/Bak À/À double knockout embryonic fibroblasts 26 and the PC3 prostate cell line. 27 Autophagy contributes to cell death in connection with the inhibition of apoptosis, improving tumor cell killing. 28 Moreover, in our study, Res induced a substantial arrest of the cell cycle in the S phase.…”

EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors

“…8,14 In vitro studies have already established the potential of rapamycin in inhibiting cellular transformation and several kinds of tumors exhibiting activation of PI3-K/Akt are hypersensitive to rapamycin in vivo. 18,19 Recent preclinical evidence supports the efficiency of mTOR inhibitors in the treatment of sarcomas: rapamycin treatment resulted in reduced phosphorylation of proteins functioning downstream of mTOR and can greatly reduce the growth of cell lines from rhabdomyosarcoma, osteosarcoma, and Ewing sarcoma. 1,2,19,20 Thus, rapamycin could be a powerful therapeutic regimen in the treatment of bone and soft tissue tumors, especially if the mTOR pathway is shown to be a critical effector of growth signaling not only from EGFR, but from other growth factor receptors as well.…”