PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis

Abstract

Phosphodiesterase 4D interacting protein (PDE4DIP) is a centrosome/Golgi protein associated with cyclic nucleotide phosphodiesterases. PDE4DIP is commonly mutated in human cancers, and its alteration in mice leads to a predisposition to intestinal cancer. However, the biological function of PDE4DIP in human cancer remains obscure. Here, we report for the first time the oncogenic role of PDE4DIP in colorectal cancer (CRC) growth and adaptive MEK inhibitor (MEKi) resistance. We show that the expression of PDE4DIP is upregulated in CRC tissues and associated with the clinical characteristics and poor prognosis of CRC patients. Knockdown of PDE4DIP impairs the growth of KRAS-mutant CRC cells by inhibiting the core RAS signaling pathway. PDE4DIP plays an essential role in the full activation of oncogenic RAS/ERK signaling by suppressing the expression of the RAS GTPase-activating protein (RasGAP) neurofibromin (NF1). Mechanistically, PDE4DIP promotes the recruitment of PLCγ/PKCε to the Golgi apparatus, leading to constitutive activation of PKCε, which triggers the degradation of NF1. Upregulation of PDE4DIP results in adaptive MEKi resistance in KRAS-mutant CRC by reactivating the RAS/ERK pathway. Our work reveals a novel functional link between PDE4DIP and NF1/RAS signal transduction and suggests that targeting PDE4DIP is a promising therapeutic strategy for KRAS-mutant CRC.

The PDE4DIP-AKAP9 axis promotes lung cancer growth through modulation of PKA signalling

“…The MTT assay was performed to determine cell viability as described previously [29]. Cell proliferation was monitored using a RTCA system (ACEA-Biosciences, San Diego, CA, USA).…”

“…IHC was performed as described previously [29]. In brief, tumour tissues were depara nized and subjected to antigen retrieval.…”

“…The ubiquitination assay was performed as described previously [29]. In brief, cells were transfected with the HA-Ubiquitin plasmid.…”

“…PDE4DIP coordinates with AKAP9 to stabilize PKA RIIα at the Golgi A-kinase anchoring proteins (AKAPs) determine the spatial and temporal aspects of PKA activation by tethering the PKA holoenzyme to distinct cellular compartments [35]. Previously, we and others reported that PDE4DIP localizes predominantly to Golgi networks by interacting with AKAP9 and that the expression of these two proteins is mutually dependent [19,29]. In NSCLC cells, silencing of PDE4DIP resulted in a signi cant decrease in the AKAP9 protein level, and knocking down AKAP9 reduced the protein level of PDE4DIP (Fig.…”

“…Recently, we reported for the rst time that PDE4DIP functions as a proto-oncogene in colorectal cancer growth and chemoresistance by regulating the RAS signalling axis in KRAS-mutant colorectal cancer [29].…”