Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy

  title={Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy},
  author={Hans-Guido Wendel and Elisa de Stanchina and Jordan S. Fridman and Abba Malina and Sagarika Ray and Scott C. Kogan and Carlos Cordon-Cardo and Jerry Pelletier and Scott W. Lowe},
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… 

Altered Apoptosis in AML

Three different approaches for overcoming apaptotic resistance have been proposed, including administering “pro-apoptotic” agents that directly inhibit anti-APoptotic molecules such as Bcl-2 or XIAP and employing cytotoxic cytolines that, in contrast to most currectly employed antileukemic agents, trigger apoptosis through the death receptor pathway.

Mammalian Target of Rapamycin Promotes Vincristine Resistance through Multiple Mechanisms Independent of Maintained Glycolytic Rate

It is concluded that mTOR activity can promote resistance through multiple mechanisms independent of maintained glycolytic rate, and that survival and metabolic control are separable.

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

Although rapamycin and novel rapalogs are usually cytostatic and not cytotoxic for leukemic cells, novel inhibitors that target the kinase activities of PI3K and mTOR may prove more effective for leukemia therapy.

Mammalian target of rapamycin (mTOR) pathway signalling in lymphomas

It seems that better understanding of mTOR regulation will reveal aspects of lymphomagenesis and contribute to the development of more powerful, targeted therapies for lymphoma patients.

mTORC1 promotes survival through translational control of Mcl-1

It is demonstrated that loss of TSC2 in the Eμ-myc murine lymphoma model leads to mTORC1 activation and accelerated oncogenesis caused by a defective apoptotic program despite compromised AKT phosphorylation, and identified myeloid cell leukemia sequence 1 (Mcl-1), a bcl-2 like family member, as a translationally regulated genetic determinant of m TORC1-dependent survival.

Reversing Drug Resistance In Vivo

In vivo validation for a strategy to reverse drug resistance in human cancers and the potential role of translational deregulation in oncogenesis and resistance are provided, illustrating the importance of tailoring cancer therapy based on tumor genotype.

Chemo- and Radiosensitization Through Inhibition of PI3K/Akt Signaling

Targeting the PI3K/Akt pathway demonstrates marked efficacy in preclinical models and has emerged as a high-quality therapeutic target in cancer treatment.

Oncogenic Roles of the PI3K/AKT/mTOR Axis.

Possible mechanisms by which the PI3K/AKT/mTOR axis contributes to oncogenic transformation include stimulation of proliferation, survival, metabolic reprogramming, and invasion/metastasis, as well as suppression of autophagy and senescence.

Targeting of the PI3K/AKT/mTOR pathway in human prostate cancer

It is demonstrated that targeting the PI3K/AKT/mTOR pathway triggers activation of the Ras/MEK/ERK compensatory pathway and therefore blockade of one pathway is not sufficient to treat prostate cancer.



Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells.

Rapamycin and CCI-779, by interacting with downstream intermediates in the phosphatidylinositol 3'-kinase/Akt signaling pathway, reverse the resistance to doxorubicin conferred by PTEN mutation/AKT activation.

Targeting mTOR signaling for cancer therapy.

Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR

In vitro and in vivo studies of isogenic PTEN+/+ and PTEN−/− mouse cells as well as human cancer cells with defined PTEN status showed that the growth of PTEN null cells was blocked preferentially by pharmacologic FRAP/mTOR inhibition, indicating that FRAP-mTOR functions downstream of Akt in tumorigenesis.

PTEN Protects p53 from Mdm2 and Sensitizes Cancer Cells to Chemotherapy*

The PTEN tumor suppressor protein inhibits phosphatidylinositol 3-kinase (PI3K)/Akt signaling that promotes translocation of Mdm2 into the nucleus. When restricted to the cytoplasm, Mdm2 is degraded.

Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells.

This work reports that rapamycin, a specific inhibitor of mTOR kinase, induces G1 cell cycle arrest and apoptosis in two rhabdomyosarcoma cell lines (Rh1 and Rh30) under conditions of autocrine cell growth, and is the first to indicate thatRapamycin-induced apoptosis is mediated by inhibition of m TOR.

Translational Control of the Antiapoptotic Function of Ras*

It is established that eIF4E-dependent protein synthesis is essential for survival of fibroblasts bearing oncogenic Ras and support the concept that activation of cap-dependent translation by extracellular ligands or intrinsic survival signaling molecules suppresses apoptosis, whereas synthesis of proteins mediating apoptosis can occur independently of the cap.

Akt and Bcl-xL Promote Growth Factor-independent Survival through Distinct Effects on Mitochondrial Physiology*

A comparison of Akt- and Bcl-xL-dependent cell survival was undertaken using interleukin-3-dependent FL5.12 cells, and it is shown that Akt and B cl-x L suppress mitochondrion-initiated apoptosis by distinct mechanisms.

An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice

It is shown that transformed cells of PTEN+/− mice have elevated levels of phosphorylated Akt and activated p70/S6 kinase associated with an increase in proliferation and that inhibition of these proteins may be therapeutic for cancer patients with deranged PI3K signaling.

Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse

It is shown that the concomitant inactivation of one Pten allele and one or both Cdkn1b alleles accelerates spontaneous neoplastic transformation and incidence of tumors of various histological origins in Pten+/−/CdKn1b−/− mice.