Blockade of AMPK-Mediated cAMP–PKA–CREB/ATF1 Signaling Synergizes with Aspirin to Inhibit Hepatocellular Carcinoma

Abstract

Aspirin can prevent or inhibit inflammation-related cancers, such as colorectal cancer and hepatocellular carcinoma (HCC). However, the effectiveness of chemotherapy may be compromised by activating oncogenic pathways in cancer cells. Elucidation of such chemoresistance mechanisms is crucial to developing novel strategies to maximize the anti-cancer effects of aspirin. Here, we report that aspirin markedly induces CREB/ATF1 phosphorylation in HCC cells, which compromises aspirin’s anti-HCC effect. Inhibition of AMP-activated protein kinase (AMPK) abrogates the induction of CREB/ATF1 phosphorylation by aspirin. Mechanistically, activation of AMPK by aspirin results in decreased expression of the urea cycle enzyme carbamoyl-phosphate synthase 1 (CPS1) in HCC cells and xenografts. Treatment with aspirin or CPS1 knockdown stimulates soluble adenylyl cyclase expression, thereby increasing cyclic AMP (cAMP) synthesis and stimulating PKA–CREB/ATF1 signaling. Importantly, abrogation of aspirin-induced CREB/ATF1 phosphorylation could sensitize HCC to aspirin. The bis-benzylisoquinoline alkaloid berbamine suppresses the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), leading to protein phosphatase 2A-mediated downregulation of CREB/ATF1 phosphorylation. The combination of berbamine and aspirin significantly inhibits HCC in vitro and in vivo. These data demonstrate that the regulation of cAMP-PKA-CREB/ATF1 signaling represents a noncanonical function of CPS1. Targeting the PKA–CREB/ATF1 axis may be a strategy to improve the therapeutic effects of aspirin on HCC.

Discovery of a Carbamoyl Phosphate Synthetase 1–Deficient HCC Subtype With Therapeutic Potential Through Integrative Genomic and Experimental Analysis

“…( 28 ) Moreover, Zhang et al demonstrated that AMPK‐mediated CPS1 depletion activated cAMP– protein kinase A–cAMP response element‐binding protein/activating transcription factor 1 signaling in HCC cells. ( 29 ) The mechanism of CPS1 dysregulation is complex, and the detrimental effects of CPS1 depletion on HCC remain to be characterized. In this study, we found that hypermethylation‐mediated CPS1‐deficient HCC cells exhibited a distinctive metabolic type due to UCD, leading to deceleration of the TCA cycle, higher ATP levels, and higher dependency on FAO.…”

Chemotherapy Resistance: Role of Mitochondrial and Autophagic Components

“…In normal biological conditions, autophagy operates at a basal rate to preserve cellular viability and homeostasis [299]. When autophagy is disrupted by chemotherapy or other environmental stresses, several pathways influence autophagy for cell death (cytotoxic autophagy) or adaptation and survival (cytoprotective autophagy), including the mTOR, phosphoinositide-dependent protein kinase B/AKT (PKB/AKT) pathway, AMP-activated protein kinase (AMPK), tumor suppressor 53 pathway, mitogen-activated protein kinase (MAPK) signaling, FOXO3A-PUMA signaling, and the ER stress pathway (Figure 5) [300][301][302][303][304][305][306][307][308][309][310][311][312].…”

The Role of TRIP6, ABCC3 and CPS1 Expression in Resistance of Ovarian Cancer to Taxanes

“…CPS1 knockdown stimulates soluble adenylyl cyclase expression, thereby increasing cyclic AMP (cAMP) synthesis and stimulating PKA-CREB/ATF1 signaling. Regulation of cAMP-PKA-CREB/ATF1 signaling represents a non-canonical function of CPS1, and targeting of the PKA-CREB/ATF1 axis may improve the therapeutic effects of aspirin in hepatocellular carcinoma [ 60 ]. Combining knockdown of CPS1 with EGFR inhibition reduces cell proliferation and impedes cell-cycle progression.…”