Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy

Abstract

Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro. Nevertheless, how Akt disables apoptosis and its contribution to clinical drug resistance are unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's action in tumorigenesis and drug resistance, but is unable to confer sensitivity to rapamycin and chemotherapy. These results establish Akt signalling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity in a genotype-dependent manner.

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…[76][77][78][79][80][81] However, more recent investigations did not confirm these findings. [76][77][78][79][80][81] Nevertheless, Akt also phosphorylates proline-rich Akt-substrate-40 (PRAS40), an inhibitor of mTORC1, and by doing so, it prevents the ability of PRAS40 to suppress mTORC1 signaling (recently reviewed in refs. 2,[79][80][81] ).…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…158 The fact that strong immunostaining for Akt has been associated with a poor prognosis in breast cancer patients independent of adjuvant therapy [159][160][161] indicates a general prognostic role for activation of the PI3K/Akt system in breast cancer. Notably, experimental evidence has linked activation of the Akt/mTOR pathway to a number of biological processes; overexpressing Akt has been shown to enhance lymphangiogenesis and confer resistance to cyclophosphamide as well as doxorubicin in murine models, 162 effects that are reversed by blocking Akt's downstream effector mTOR by rapamycin. Further, mTOR inhibitors like rapamycin and everolimus have been shown to inhibit growth of triple-negative breast cancer cell lines, reverse doxorubicin resistance and enhance docetaxel effects in vitro.…”

Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation

“…Recent advances in cancer research have drawn increased interest in the use of mTOR inhibitors to treat various cancers. Indeed, rapamycin was shown to sensitize cancer cells to cytotoxic therapies (Wendel et al, 2004), and some rapamycin analogs are in clinical development for cancer treatment (Amaravadi and Thompson, 2005).…”