The dysregulated expression and functional effect of CaMK2 in cancer

Abstract

CaMK2 (calcium/calmodulin-dependent protein kinase 2), a multifunctional serine/threonine-protein kinase involved in diverse cellular processes, is vital for the transduction of the Ca²⁺ signaling cascade. Recently, research has highlighted the involvement of CaMK2 in cancer development. However, the specific effects of CaMK2 on cancer have not been fully elucidated. In this review, we summarize not only the altered expression of CaMK2 in a range of cancers, as evidenced by bioinformatics analysis, but also the significant role of CaMK2 in regulating cancer progression, such as proliferation and metastasis. In addition, we described the functional influence of CaMK2 on cancer stemness and resistance. Understanding the critical effects and mechanisms of CaMK2 in cancer would facilitate the development of a promising therapeutic strategy for cancer treatment.

Keywords: CaMK2; Cancer; Metastasis; Proliferation; Resistance; Stemness.

Fig. 1

CaMK2 regulates the growth, metastasis, stemness and drug resistance of cancer by targeting multiple downstream substrates. A The activation of FAK, STAT5 and AKT are responsible for the stimulative effects of CAMK2 on celluar grwoth, migration and invasion in breast cancer [43]. B CaMK2γ accelerates the stem-like properties of lung cancer cells in an Akt- and β-catenin-dependent manner [69]. C CaMK2γ promotes myeloid leukemia cells proliferation through activation of p44/42 MAPK, p38 MAPK, STAT3, STAT5 and β-catenin [56]. D CaMK2γ facilitates the proliferation, migration and metastasis of colon cancer by activating several pathways including AKT, p38 MAPK and ERK1/2 [40]. E CaMK2γ enhances the growth, metastasis and stem-like traits of GSCs through upregulation of AKT, STAT3 and ERK1/2 pathways by activating c-Met signaling [66]. F CaMK2α maintains the breast CSCs survival in glucose-deprived conditions through SERCA induction by activating NF-kB [68]. G The activation of AKT, NF-kB, mTOR and S6 are required for the CaMK2β-mediated growth and migration of gastric adenocarcinoma cells [46]. H CaMK2 may promote hepatoma Cells development by AKT-dependent upregulation of HIF-1α [47]. I CaMK2 may induce resistance to doxorubicin in human colon cancer cells via activation of HIF-1α and Pgp [70]. J The functions of CaMK2 in promoting the celluar proliferation and invasion of prostate cancer are associated with the upregulation of Notch-1 signaling and its downstream substrates containing Hes-1 and c-Myc [49]. K CaMK2γ promotes T cell lymphoma by directly phosphorylating and stabilizing c-Myc protein [58]. The software used to generate the Figure is Microsoft Office PowerPoint (Office 2019 version). The signal network presented in this Figure is summarized from these experimental articles that included in this narrative review. CRCs colorectal cancer, GSCs glioblastoma stem-like cells, GACs gastric adenocarcinoma cells, CSCs cancer stem cells