Abstract
Src family kinases (SFKs) are non-receptor kinases that play a critical role in the pathogenesis of colorectal cancer (CRC). The expression and activity of SFKs are upregulated in patients with CRC. Activation of SFKs promotes CRC cell proliferation, metastases to other organs and chemoresistance, as well as the formation of cancer stem cells (CSCs). The enhanced expression level of Src is associated with decreased survival in patients with CRC. Src-mediated regulation of CRC progression involves various membrane receptors, modulators, and suppressors, which regulate Src activation and its downstream targets through various mechanisms. This review provides an overview of the current understanding of the correlations between Src and CRC progression, with a special focus on cancer cell proliferation, invasion, metastasis and chemoresistance, and formation of CSCs. Additionally, this review discusses preclinical and clinical strategies to improve the therapeutic efficacy of drugs targeting Src for treating patients with CRC.
Highlights
The purification of v-Src from Rous sarcoma virus (RSV), which activates the insulin receptor, led to the identification of various Src family kinases (SFKs) [1,2], such as Src, Fyn, Yes, Yrk, Fgr, Hck, Blk, lymphocyte-specific protein tyrosine kinase (Lck), and Lyn
An Src inhibitor, and oxaliplatin are approved by the Food and Drug Administration (FDA) for treating chronic myeloid leukemia (CML) (ClinicalTrials.gov identifier: NCT01460160) and colon cancer (ClinicalTrials.gov identifier: NCT00017082), respectively
Tumor progression is regulated by SFKs through highly complex mechanisms
Summary
The purification of v-Src (pp60src) from Rous sarcoma virus (RSV), which activates the insulin receptor, led to the identification of various Src family kinases (SFKs) [1,2], such as Src, Fyn, Yes, Yrk, Fgr, Hck, Blk, lymphocyte-specific protein tyrosine kinase (Lck), and Lyn. The expression levels of Src and Tyr380-phosphorylated caspase-8 were reported to be upregulated in 80% and 82.6% of patients with CRC, respectively, [18]. Tyrosine Kinase (ERBB4), which was reported to be upregulated in 43% of patients with CRC, results in the upregulation of cyclooxygenase 2 (COX2) expression, which enhances the proliferation of CRC cells [19,20]. EGF-induced Src activation enhances the localization of pseudopodium-enriched atypical kinase 1 (PEAK1), which was reported to be markedly upregulated in 81% of patients with CRC, to the actin cytoskeleton and focal adhesion. Wnt-β-catenin signaling by Src-induced Rac, which enhances reactive oxygen species (ROS) generation, tyrosine kinase receptors, including EGFR, is reported to be involved in the pathogenesis of cancer results in enhanced [23]. Advanced stages of CRC are associated with markedly higher Eps expression levels
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