Synergistic Anti-Cancer Effects of AKT and SRC Inhibition in Human Pancreatic Cancer Cells

Abstract

PurposeTo investigate the effect of combined inhibition of protein kinase B (AKT) and SRC on the growth and metastatic potential of human pancreatic cancer cells.Materials and MethodsAKT and SRC were inhibited using 10-DEBC and PP2, respectively. The expression of their messenger RNAs were down-regulated by specific small interfering RNA (siRNA). Changes in pancreatic cancer cell growth and metastatic potential were determined using a cell viability assay and a xenotransplant model of pancreatic cancer, as well as cell migration and invasion assays. Signal proteins were analyzed by Western blot.ResultsThe inhibitors 10-DEBC and PP2 suppressed cell proliferation in a dose-dependent fashion in pancreatic cancer cell lines MIA PaCa-2 and PANC-1. The simultaneous inhibition of AKT and SRC at low concentrations resulted in a significant suppression of cell proliferation. Knockdown of AKT2 and SRC using siRNAs also significantly decreased cell proliferation. In a pancreatic cancer model, combined treatment with 10-DEBC and PP2 also significantly suppressed the growth of pancreatic cancer. Application of 10-DEBC with PP2 significantly reduced the metastatic potential of pancreatic cancer cells by inhibiting migration and invasion. The combined inhibition suppressed the phosphorylation of mTOR and ERK in pancreatic cancer cells.ConclusionCombined targeting of AKT and SRC resulted in a synergistic efficacy against human pancreatic cancer growth and metastasis.

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases

“…Several kinases consistently identified as differentially active across multiple pipelines, cell lines, or final combinatorial analyses recapitulate kinases previously identified as playing well-established roles in a variety of human cancer pathologies. These kinases include insulin receptor (INSR) kinase [ 37 , 38 ] ( Figure 2 and Figure 3 , Table 3 and Table 4 ), EPHA2 kinase [ 29 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ] ( Figure 2 and Figure 3 , Table 4 ), platelet-derived growth factor receptor alpha (PDGFRA) kinase [ 47 , 48 , 49 , 50 , 51 ] ( Figure 2 and Figure 3 , Table 1 , Table 2 , Table 3 and Table 4 ), SRC kinase [ 26 , 27 , 52 , 53 , 54 , 55 , 56 , 57 ] ( Figure 2 and Figure 3 , Table 1 , Table 2 , Table 3 and Table 4 ), and tyrosine kinase nonreceptor 2 (TNK2) kinase [ 58 , 59 , 60 , 61 , 62 , 63 , 64 ...…”

Mitophagy-Related Gene Signature for Prediction Prognosis, Immune Scenery, Mutation, and Chemotherapy Response in Pancreatic Cancer

“…SRC is a nonreceptor tyrosine kinase responsible for tumor cell apoptosis, migration, and transformation (Fianco et al, 2016). SRC has been reported to be highly expressed in PC samples (Castillo et al, 2020), and activation of SRC contributes to PC tumorigenicity (Ahn et al, 2018). VDAC1 mainly participated in cell volume regulation and apoptosis (Shoshan-Barmatz et al, 2020).…”

Insights into Functional Connectivity in Mammalian Signal Transduction Pathways by Pairwise Comparison of Protein Interaction Partners of Critical Signaling Hubs

“…These two signaling hubs share 9 interaction partners including the module containing critical nodes SRC and MTOR Kinases ( Figure 8B). Furthermore, inhibition of these Kinases can be used in combination to target both pathways in some cancers [64]. Two Serine Kinases STK39 and AKT1 share the same interaction Protein Kinase, p38 or MAPK14 (Table 4).…”