Targeting the cyclin-dependent kinase 5 in metastatic melanoma

Abstract

The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5 is dispensable for the growth of primary tumors. However, we observed that ablation of CDK5 completely abrogated the metastasis, revealing that CDK5 is essential for the metastatic spread. In mouse and human melanoma cells CDK5 promotes cell invasiveness by directly phosphorylating an intermediate filament protein, vimentin, thereby inhibiting assembly of vimentin filaments. Chemical inhibition of CDK5 blocks the metastatic spread of patient-derived melanomas in patient-derived xenograft (PDX) mouse models. Hence, inhibition of CDK5 might represent a very potent therapeutic strategy to impede the metastatic dissemination of malignant cells.

RETRACTED ARTICLE: Genipin suppression of growth and metastasis in hepatocellular carcinoma through blocking activation of STAT-3

“…A patient-derived xenograft (PDX) mice model may retain more similarities to human cancers compared to a normal cell-line xenograft mice model. Previous studies have shown that PDX mice models may be useful for screening novel anti-cancer agents [ 31 ]. Herein, seven human surgical HCC tissue samples along with the peripheral normal liver tissues were collected from primary HCC patients (Supplementary Table 1 ).…”

The Role of CDK5 in Tumours and Tumour Microenvironments

“…This secretion can promote inflammation, leading to tumour development and metastasis [ 193 ]. In line with this, in melanoma, CDK5 could directly phosphorylate vimentin at Ser 56 [ 194 ]. The decreased kinase activity of CDK5 leads to blocking the metastasis by losing both phosphorylation form of vimentin and soluble vimentin [ 194 ].…”

“…In line with this, in melanoma, CDK5 could directly phosphorylate vimentin at Ser 56 [ 194 ]. The decreased kinase activity of CDK5 leads to blocking the metastasis by losing both phosphorylation form of vimentin and soluble vimentin [ 194 ]. This suggests that CDK5 can regulate inflammation factors conducive to the development of cancer.…”

“…However, other groups reported that CDK5 inhibits proliferation and migration of cancer cells. Recently, Sharma et al have utilised the melanoma cells expressing analogue-sensitive CDK5, which made it possible to specifically inhibit CDK5 in cancer cells, clearly demonstrating that inhibition of CDK5 in melanoma cells inhibits the metastatic spread of melanoma [ 194 ].…”

Genipin Suppresses Growth and Metastasis in Hepatocellular Carcinoma Through Blocking Activation of STAT-3

“…Patient-derived xenograft (PDX) mice model may keep more similarities to the human cancers compared to normal cell-lines xenograft mice model. Previous studies have shown that PDX mice model may be useful for screening novel anti-cancer agents [30]. Herein, seven human surgical HCC tissue samples along with the peripheral normal liver tissues were collected from primary HCC patients (supplementary table 1).…”