Inhibition of the PI 3‐kinase pathway disrupts the unfolded protein response and reduces sensitivity to ER stress‐dependent apoptosis

Abstract

Class Ia phosphoinositide 3‐kinases (PI3K) are critical mediators of insulin and growth factor action. We have demonstrated that the p85α regulatory subunit of PI3K modulates the unfolded protein response (UPR) by interacting with and regulating the nuclear translocation of XBP‐1s, a transcription factor essential for the UPR. We now show that PI3K activity is required for full activation of the UPR. Pharmacological inhibition of PI3K in cells blunts the ER stress‐dependent phosphorylation of IRE1α and PERK, decreases induction of ATF4, CHOP, and XBP‐1 and upregulates UPR target genes. Cells expressing a human p85α mutant (R649W) previously shown to inhibit PI3K, exhibit decreased activation of IRE1α and PERK and reduced induction of CHOP and ATF4. Pharmacological inhibition of PI3K, overexpression of a mutant of p85α that lacks the ability to interact with the p110α catalytic subunit (∆p85α) or expression of mutant p85α (R649W) in vivo, decreased UPR‐dependent induction of ER stress response genes. Acute tunicamycin treatment of R649W+/− mice revealed reduced induction of UPR target genes in adipose tissue, whereas chronic tunicamycin exposure caused sustained increases in UPR target genes in adipose tissue. Finally, R649W+/− cells exhibited a dramatic resistance to ER stress‐dependent apoptosis. These data suggest that PI3K pathway dysfunction causes ER stress that may drive the pathogenesis of several diseases including Type 2 diabetes and various cancers.

ER Stress Response Failure and Steatohepatitis Comorbid with Diabetes

“…In model mice of obesity and diabetes, however, insulin-mediated nuclear translocation of XBP-1 s protein is impaired due to insulin resistance [25,26]. A similar insulin signaling-mediated nuclear translocation of XBP-1 s protein was recently reported in other tissues as well [27]. Interestingly, XBP-1 s protein regulates gluconeogenesis rather directly, via ubiquitination and consequent proteasome-mediated degradation of FoxO1, a transcription factor involved in the induction of gluconeogenic enzymes in the liver [28] (Figure 3).…”

ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents

“…SHORT syndrome (short stature, hypermobility of joints, ocular depression, Rieger's anomaly, teething delay) with partial lipodystrophy, is caused by a hot spot mutation in PIK3R1 which has a central role in the insulin‐signaling pathway and growth factor resistance 246–248 . Mutation carriers of the dominant‐negative mutation in PIK3R1 seem to be protected from obesity and hepatic steatosis but not diabetes, 249 and the disease mechanisms is associated with unfolded protein response and reduced sensitivity to ER stress‐dependent apoptosis 250 …”

“…[246][247][248] Mutation carriers of the dominant-negative mutation in PIK3R1 seem to be protected from obesity and hepatic steatosis but not diabetes, 249 and the disease mechanisms is associated with unfolded protein response and reduced sensitivity to ER stress-dependent apoptosis. 250 The mainstay of therapy for lipodystrophy is dietary intervention with a low-fat, calorie-neutral diet, 241 and an expert dietician as part of the multidisciplinary team is of paramount importance. In partial lipodystrophy, insulin sensitizers such as metformin and glitazones may be initially effective 251 but glitazones may exacerbate accumulation of ectopic fat in the face and neck.…”

Endoplasmic Reticulum Stress and Tumor Microenvironment in Bladder Cancer: The Missing Link

“…Mounting evidence have suggested that the genetic alterations of classical cellular signaling pathways can also trigger ERS, and the three parallel yet distinctive UPR pathways interplay with them to determine oncogenic transformation and cell fate. For example, in brown adipocytes of hepatocellular carcinoma (HCC), the inhibition of the PI3K/AKT pathway leads to decreased levels of PERK phosphorylation; downregulates the expression of ATF4 and CHOP; decreases the phosphorylation levels of IRE1, GRP78, and XBP1; and antagonizes the effects of the ERS inducer tunicamycin (Winnay et al, 2020). In addition, PI3K/AKT has been found to positively regulate UPR in a lung fibrosis model (Hsu et al, 2017).…”