Interplay between PI3K/Akt and MAPK signaling pathways in DNA-damaging drug-induced apoptosis

Abstract

In order to elucidate the role of the mitogen-activated protein kinases, including JNK, p38 MAPK and ERK, as well as the survival-associated PI3K/Akt signaling pathway, in the response to chemotherapy, we have conducted a comparative study regarding the effects of doxorubicin on these pathways. Doxorubicin was determined to elicit the apoptosis of NIH3T3 cells in a dose-dependent manner. Prior to cell death, both Akt and p38 MAPK were transiently activated, and subsequently inactivated almost wholly, whereas ERK and JNK evidenced sustained activations in response to the drug treatment. The inhibition of PI3K/Akt and p38 MAPK both accelerated and enhanced doxorubicin-induced apoptosis and ERK inhibition apparently exerted negative effect on apoptosis. The modulation of PI3K/Akt activation by treatment of LY294002 or expression of Akt mutants such as Akt-DN or Myr-Akt exerted a significant effect on the activation of ERK1/2. We also observed that PI3K/Akt and sustained ERK activation were associated intimately with the etoposide-induced apoptosis. Taken together, our results clearly suggest that the differential regulation of the PI3K/Akt, ERK1/2, and p38 MAPK signaling pathways are crucial in the context of DNA-damaging drug-induced apoptosis, and this has compelled us to propose that the sustained activation of ERK1/2 pathway may be generally involved in the apoptosis induced by anticancer DNA-damaging drugs, including doxorubicin and etoposide.

Stimulated PI3K-AKT Signaling Mediated through Ligand or Radiation-Induced EGFR Depends Indirectly, but not Directly, on Constitutive K-Ras Activity

“…EGFR signaling into the PI3K-AKT pathway has been shown by many authors to be an important step in cell survival following exogenous cellular stress, such as exposure to ionizing radiation and chemotherapy (56)(57)(58). One important mechanism of AKT signaling to promote cell survival is the blockage of apoptosis through inactivation of the Bad protein, an important component of the mitochondrial apoptotic pathway (27).…”

Activation of the PI3K/Akt and MAPK signaling pathways antagonizes adriamycin-induced HL-60 leukemia cell apoptosis

“…it has been reported that adM resistance in solid tumors results not only from the inactivation of apoptotic pathways, but also from the over-activation of survival signals (10,11). The phosphoinositide 3 kinase (Pi3K)/akt pathway is probably the best characterized and most prominent pathway with regard to the transmission of anti-apoptotic signals in cell survival, and is activated by exposure to most chemotherapeutic agents, including adM and etoposide (12,13), in gastric and breast cancer (14)(15)(16).…”

Apoptosis‐induced inhibition of CD1d‐mediated antigen presentation: different roles for caspases and signal transduction pathways

“…8 In concert with other signal transduction pathways, MAPK transduce these changes into alterations in gene expression and the regulation of various cellular functions. 9 Ceramide is an important second messenger during apoptosis and induces apoptosis via both caspase-dependent and-independent pathways. [10][11][12] Strategies to promote the intracellular accumulation of ceramide may thus have therapeutic utility.…”