HEATR1 Negatively Regulates Akt to Help Sensitize Pancreatic Cancer Cells to Chemotherapy

Abstract

Elucidating mechanisms of chemoresistance is critical to improve cancer therapy, especially for the treatment of pancreatic ductal adenocarcinoma (PDAC). Genome-wide association studies have suggested the little studied gene HEATR1 as a possible determinant of cellular sensitivity to different chemotherapeutic drugs. In this study, we assessed this hypothesized link in PDAC, where HEATR1 expression is downregulated significantly. HEATR1 silencing in PDAC cells increased resistance to gemcitabine and other chemotherapeutics, where this effect was associated with increased AKT kinase phosphorylation at the Thr308 regulatory site. Mechanistically, HEATR1 enhanced cell responsiveness to gemcitabine by acting as a scaffold to facilitate interactions between AKT and the protein phosphatase PP2A, thereby promoting Thr308 de-phosphorylation. Consistent with these findings, treatment with the AKT inhibitor TCN sensitized HEATR1-depleted PDAC cells to gemcitabine, suggesting this therapeutic combination may overcome gemcitabine resistance in patients with low HEATR1 expression. Clinically, we found that HEATR1 downregulation in PDAC patients was associated with increased AKT phosphorylation, poor response to tumor resection plus gemcitabine standard-of-care treatment and shorter overall survival. Collectively, our findings establish HEATR1 as a novel regulator of AKT and a candidate predictive and prognostic indicator of drug responsiveness and outcome in PDAC patients.

PROM2 promotes gemcitabine chemoresistance via activating the Akt signaling pathway in pancreatic cancer

“…Resistance is a major cause of treatment failure in chemotherapy among cancer patients 42,43 . There are several signaling pathways, including Akt pathway, MAPK, Bcl-2, and MMP13 pathways, involved with gemcitabine chemoresistance in pancreatic cancer 13,44 . Though previous reports have suggested that MUC1, MUC4, and DNA-PKcs might enhance pancreatic cancer chemoresistance [45][46][47] , the underlying mechanism remains largely unknown.…”

“…Constitutive activation of the Akt signaling pathway occurs in various cancer types and confers chemoresistance 13,[36][37][38] . To determine whether PROM2 promotes chemoresistance via modulation of the Akt pathway, GSEA enrichments were executed and revealed PROM2 expression positively correlated with the Akt signaling pathway related gene signature (Fig.…”

“…Deregulation of the Akt signaling pathway is a frequent occurrence in pancreatic cancer and is significantly correlated with gemcitabine chemoresistance 13,14 . Akt activity is tightly controlled: it is activated by growth factors or cellular stress in the cytoplasm, and then recruited to the plasma membrane where it is phosphorylated (at Thr308 and Ser473) [15][16][17] .…”

“…Activated Akt can also phosphorylate Caspase-9 and impair its function in the apoptotic cascade 20,21 . Above all, constructive activation of the Akt signaling pathway can protect cells from drug-induced apoptosis and contribute to chemoresistance 13,22,23 . Thus, identifying potential modulators of the Akt signaling pathway would be crucial in restraining gemcitabine chemoresistance.…”

The Antibiotic Drug Tigecycline: A Focus on its Promising Anticancer Properties

“…PTEN is a negative modulator of the Akt signaling pathway, and inhibition of PTEN by a small-molecule inhibitor could significantly activate Akt (Shojaee et al, 2016). Similarly, PP2A can down-regulate Akt activation by directly promoting Thr308 dephosphorylation (Liu et al, 2016). Additionally, once Akt is locked in the active confirmation, it can regulate more than 100 down-stream factors that are involved in diverse cellular functions, including cell proliferation, apoptosis, metabolism, and so on.…”