Blocking Myristoylation of Src Inhibits Its Kinase Activity and Suppresses Prostate Cancer Progression

Abstract

Protein N-myristoylation enables localization to membranes and helps maintain protein conformation and function. N-myristoyltransferases (NMT) catalyze co- or post-translational myristoylation of Src family kinases and other oncogenic proteins, thereby regulating their function. In this study, we provide genetic and pharmacological evidence that inhibiting the N-myristoyltransferase NMT1 suppresses cell cycle progression, proliferation and malignant growth of prostate cancer cells. Loss of myristoylation abolished the tumorigenic potential of Src and its synergy with androgen receptor in mediating tumor invasion. We identified the myristoyl-CoA analog B13 as a small molecule inhibitor of NMT1 enzymatic activity. B13 exposure blocked Src myristoylation and Src localizaiton to the cytoplasmic membrane, attenuating Src-mediated oncogenic signaling. B13 exerted its antiinvasive and antitumor effects against prostate cancer cells with minimal toxic side-effects in vivo. Structural optimization based on structure-activity relationships enabled the chemical synthesis of LCL204 with enhanced inhibitory potency against NMT1. Collectively, our results offer a preclincal proof of concept for the use of protein myristoylation inhibitors as a strategy to block prostate cancer progression.

Dietary palmitate cooperates with Src kinase to promote prostate tumor progression

“…Lentiviral vector for overexpression of Src(WT), Src(Y529F), Src(WT) + AR, and AR were constructed as previously reported using the FUCRW parental vector . The TRE/Src(Y529F) doxycycline‐inducible lentiviral vector was previously created using pTK380 as a parental vector .…”

“…Therefore, the created lentiviral vector‐expressed c‐Src under the ubiquitin promoter and AR under the cytomegalovirus promoter without red fluorescent protein (RFP) or green fluorescent protein markers. The short hairpin RNA (shRNA)‐Src construct was used to knockdown the human Src gene as previously reported . Lentiviral production and infection were performed as described previously .…”

“…The activation of Src kinase promotes cell survival, proliferation, migration, and invasion in cancer development, and facilitates epithelial‐to‐mesenchymal transition during cancer progression . Our previous study indicated that overexpression of Src kinase synergizes with androgen receptor (AR) in promoting prostate tumorigenesis . Additionally, Src‐mediated AR activation promotes the development of androgen‐independent prostate cancer .…”

Emerging Roles of Fibroblast Growth Factor 10 in Cancer

“…In vitro studies showed that loss of Src myristoylaton had a significant inhibitory effect on FGF10-induced oncogenic signaling in comparison with a kinase-dead Src mutant ( Li et al, 2018b ). These data have prompted efforts to develop an N-myristoyltransferase inhibitor as a means to therapeutically target the FGF10/FGFR/Src signaling axis in cancer ( French et al, 2004 ; Thinon et al, 2014 ; Kim et al, 2017 ).…”

Paracrine Fibroblast Growth Factor Initiates Oncogenic Synergy with Epithelial FGFR/Src Transformation in Prostate Tumor Progression

“…Myristoylation is an important lipid modification for Src kinase activity [32] , [33] , [34] . We further examined the role of Src myristoylation in FGF10-induced tumorigenesis in vivo .…”