Complex roles of cAMP–PKA–CREB signaling in cancer

Abstract

Cyclic adenosine monophosphate (cAMP) is the first discovered second messenger, which plays pivotal roles in cell signaling, and regulates many physiological and pathological processes. cAMP can regulate the transcription of various target genes, mainly through protein kinase A (PKA) and its downstream effectors such as cAMP-responsive element binding protein (CREB). In addition, PKA can phosphorylate many kinases such as Raf, GSK3 and FAK. Aberrant cAMP–PKA signaling is involved in various types of human tumors. Especially, cAMP signaling may have both tumor-suppressive and tumor-promoting roles depending on the tumor types and context. cAMP–PKA signaling can regulate cancer cell growth, migration, invasion and metabolism. This review highlights the important roles of cAMP–PKA–CREB signaling in tumorigenesis. The potential strategies to target this pathway for cancer therapy are also discussed.

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

“…The transcription factors CREB and its family member ATF1 may promote tumorigenesis and chemoresistance and can be activated by PKA [ 33 ]. PKA activity can be promoted by both COX-prostaglandin E2 (PGE2)-EP2 receptor signaling and AMPK [ 36 , 37 ].…”

“…About one week later, the mice with tumors were randomly divided into 4 groups, with 8 mice per group. The mice were orally administrated with aspirin (100 mg/kg/day), berbamine (50 mg/kg/day) or both as previously described [ 7 , 8 , 9 , 13 , 33 ]. The control group was treated with a vehicle.…”

“…Importantly, downregulation of CPS1 leads to an increase in the levels of cyclic AMP (cAMP) and activation of protein kinase A (PKA)-cAMP response element-binding protein (CREB)/ATF1 axis, which compromises the anti-cancer effects of aspirin. Previous studies have demonstrated that cAMP–PKA–CREB signaling has important roles in various human cancers [ 33 ]. Moreover, PKA activation is regulated by other oncogenic protein kinases, such as insulin-like growth factor receptors [ 34 ].…”

SEPHS1 promotes SMAD2/3/4 expression and hepatocellular carcinoma cells invasion

“…While the mechanisms of SMAD phosphorylation have been intensively studied, little is known about the regulation of SMAD expression. The cAMP-PKA-CREB signaling may negatively regulate TGF-β signaling by up-regulating the expression of SMAD7 [ 29 , 30 ]. In addition, the E3 ubiquitin ligase PJA1 is identified as a promoter of SMAD3 degradation [ 31 ].…”

Store-Operated Calcium Entry: Shaping the Transcriptional and Epigenetic Landscape in Pancreatic Cancer

“…Once in the nucleus, cAMP response element-binding protein (CREB) is activated upon phosphorylation of Ser133 by CAMKIV, while CAMKII can phosphorylate Ser133 or Ser142 of CREB, thereby activating or inhibiting it, respectively [60,61]. CREB hyperactivation has been tightly associated with cancer initiation, development and metastasis [62,63]. Another common target of CAMKII and CAMKIV is the serum response factor (SRF), which is activated upon phosphorylation by both enzymes [64,65], and is best characterized for driving key cell migration genes [66,67].…”