Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents

Abstract

Although Akt is known as a survival kinase, inhibitors of the phosphatidylinositol 3-kinase (PI3K)–Akt pathway do not always induce substantial apoptosis. We show that silencing Akt1 alone, or any combination of Akt isoforms, can suppress the growth of tumors established from phosphatase and tensin homologue–null human cancer cells. Although these findings indicate that Akt is essential for tumor maintenance, most tumors eventually rebound. Akt knockdown or inactivation with small molecule inhibitors did not induce significant apoptosis but rather markedly increased autophagy. Further treatment with the lysosomotropic agent chloroquine caused accumulation of abnormal autophagolysosomes and reactive oxygen species, leading to accelerated cell death in vitro and complete tumor remission in vivo. Cell death was also promoted when Akt inhibition was combined with the vacuolar H+–adenosine triphosphatase inhibitor bafilomycin A1 or with cathepsin inhibition. These results suggest that blocking lysosomal degradation can be detrimental to cancer cell survival when autophagy is activated, providing rationale for a new therapeutic approach to enhancing the anticancer efficacy of PI3K–Akt pathway inhibition.

Synergistic Myeloma Cell Death via Novel Intracellular Activation of Caspase-10–Dependent Apoptosis by Carfilzomib and Selinexor

“…6C), which may account for the rapid phenotypic changes associated with apoptosis and autophagy seen in Fig. 1B and C. Akt is cleaved during apoptosis, resulting in its inactivation and subsequent induction of autophagy (31,32). Levels of active Ser473 phosphorylated Akt increased until 8 hours, when Akt cleavage peaked, then declined to baseline levels.…”

“…We also assessed levels of total Akt and its activation state given its pivotal role in myeloma cell survival and drug resistance (30), and its ability to limit autophagy (31). Interestingly, we found simultaneous activation of caspase-10, -8, -9, and -3 and cleavage of both PARP and Akt beginning 6 hours after treatment (Fig.…”

14-3-3 Proteins regulate Akt Thr308 phosphorylation in intestinal epithelial cells

“…For instance, it could act as a switch that controls a major cellular energy consumer, mTORC1, and a major energy producer, Akt. But also could have an important role to inhibit autophagy [47][48][49][50] which is an important process to prevent autophagy-mediated cell death. 47,51 Cytokine-driven autophagy has been observed in several pathological conditions including atherosclerosis, 52 myopathy 53 and arthritis, 54 which has been linked to TNFα and IFNγ presence.…”

“…But also could have an important role to inhibit autophagy [47][48][49][50] which is an important process to prevent autophagy-mediated cell death. 47,51 Cytokine-driven autophagy has been observed in several pathological conditions including atherosclerosis, 52 myopathy 53 and arthritis, 54 which has been linked to TNFα and IFNγ presence. But, contrary to those reports where autophagy acts as a suicidal mechanism, 55,56 our results suggested that the major purpose of the accompanying increase in autophagy observed during inflammation is to fully activate Akt1, a major antiapoptotic signaling molecule.…”

Salvianolic acid A positively regulates PTEN protein level and inhibits growth of A549 lung cancer cells

“…Once in the membrane, PDK1 and mammalian target of rapamycin 1 (mTOR1) activate Akt through phosphorylation at various sites. Thus, the activated Akt positively regulated cell growth or activity, but negatively regulated cell autophagy and apoptosis (13). PTEN has been demonstrated to be the essential molecule regulating PI3K/AKT pathways and consequently various cell destinations (14).…”