Myristoylation of Src kinase mediates Src-induced and high-fat diet–accelerated prostate tumor progression in mice

Kim, Sungjin; Yang, Xiangkun; Li, Qianjin; Wu, Maomao; Costyn, Leah J.; Beharry, Zanna; Bartlett, Michael G.; Cai, Houjian

doi:10.1074/jbc.m117.798827

Cited by 43 publications

(51 citation statements)

References 38 publications

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“…The collected samples and standards were subjected to liquid chromatography‐mass spectrometry/mass spectrometry (LC‐MS/MS) analysis using an high‐performance liquid chromatography (HPLC) system (with 1100 binary pump) (Agilent, Santa Clara, CA) coupled with a Waters Micromass Quattro Micro triple Quadrupole Mass Spectrometer (Waters, Milford, MA). The details of the simultaneous detection of acyl‐CoAs and internal standard were described in previous publications …”

Section: Methodsmentioning

confidence: 99%

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Dietary palmitate cooperates with Src kinase to promote prostate tumor progression

et al. 2019

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Numerous genetic alterations have been identified during prostate cancer progression. The influence of environmental factors, particularly the diet, on the acceleration of tumor progression is largely unknown. Expression levels and/or activity of Src kinase are highly elevated in numerous cancers including advanced stages of prostate cancer. In this study, we demonstrate that high-fat diets (HFDs) promoted pathological transformation mediated by the synergy of Src and androgen receptor in vivo. Additionally, a diet high in saturated fat significantly enhanced proliferation of Src-mediated xenograft tumors in comparison with a diet high in unsaturated fat. The saturated fatty acid palmitate, a major constituent in a HFD, significantly upregulated the biosynthesis of palmitoyl-CoA in cancer cells in vitro and in xenograft tumors in vivo. The exogenous palmitate enhanced Src-dependent mitochondrial β-oxidation. Additionally, it elevated the amount of C16-ceramide and total saturated ceramides, increased the level of Src kinase localized in the cell membrane, and Src-mediated downstream signaling, such as the activation of mitogen-activated protein kinase and focal adhesion kinase. Our results uncover how the metabolism of dietary palmitate cooperates with elevated Src kinase in the acceleration of prostate tumor progression. K E Y W O R D S palmitate/fatty acid metabolism/Src kinase/prostate cancer 1 | INTRODUCTION Prostate cancer is the most common cancer in men and one of the leading causes of cancer-related deaths in developed countries. 1 Diet is considered a critical environmental risk factor in prostate cancer progression. 2 Numerous epidemiological studies indicate that obesity, higher body mass index, or adult weight gain significantly increases the risk of aggressive prostate cancer, mortality, and recurrence of prostate cancer. 3-8 A high-fat diet (HFD) or certain dietary saturated fatty acids (FAs) including palmitic acid (PA) and myristic acid (MA) are associated with advanced stages of prostate cancer and increase the risk of prostate cancer-specific mortality. 3,5,7,9 Incorporation of excess free FAs into cancer cell membranes promotes cancer invasion by reduction of cell-cell contact and increase of surface adhesion. 10 However, the interaction of dietary factors with oncogenic events to regulate tumor progression is not well-understood. Numerous genetic alterations including aberrant expression and/ or loss of tumor suppressor genes have been identified in the initiation and progression of prostate tumors. 11 Among those oncogenic events, overexpression and/or activation of Src kinase is common in advanced stages of prostate cancer. 12,13 Src kinase is a pleiotropic activator to mediate numerous signal transduction pathways initiated by G-protein coupled receptors, β1-integrin, growth factor receptors, and others. 14,15 The activation of Src kinase promotes cell survival, proliferation, migration, and invasion in The Prostate. 2019;79:896-908. wileyonlinelibrary.com/journal/pros

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Section: Methodsmentioning

confidence: 99%

“…Our previous studies have shown that a HFD accelerates Src‐mediated tumorigenesis. Particularly, dietary MA significantly increases the biosynthesis of myristoyl‐CoA, expression levels of myristoylated Src, and enhances its kinase activity . PA is a major saturated FA component in a Western diet .…”

Section: Introductionmentioning

confidence: 99%

Dietary palmitate cooperates with Src kinase to promote prostate tumor progression

et al. 2019

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“…Therefore, B13 might target tumor progression in which myristoylation is essential for the "addicted" oncogenic protein in the tumors (48). While cancer cells such as SNU16, KATO III, and MDA-MS-134-VI possess aberrant expression of FGFR1/2, other cancer cells such as PC-3 are dependent on Src kinase activity (26). B13 might serve as an agent for targeting tumor progression driven by the oncogenic pathways in which a myristoylated protein is essential to mediate the oncogenic signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Cell lysates underwent a Click reaction in which the azide functional group on myristoylated proteins was coupled to an alkyne tagged with biotin, allowing detection with streptavidin (Fig. 3C, lane 2 vs. lane 1) (26). Myristoylation is essential for the localization of FRS2α.…”

Section: A Myristoyl-coa Analog B13 Suppresses the Myristoylation Omentioning

confidence: 99%

Pharmacologically targeting the myristoylation of the scaffold protein FRS2α inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression

Li¹,

Alsaidan²,

Ma³

et al. 2018

Journal of Biological Chemistry

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“…Src is a myristoylated protein and can be found both within and outside of lipid rafts, as well as within endosomes, before translocating to the plasma membrane (Seong et al, 2009). Src can be activated by exogenous saturated fatty acids, such as palmitate and myristic acid, or the overexpression of cluster of differentiation 36 (CD36, also named fatty acid translocase), which is known to facilitate long-chain fatty acid uptake through the myristoylation of Src, leading to activation of its downstream signalling, such as JNK signalling (Holzer et al, 2011;Huang et al, 2017;Kim et al, 2017Kim et al, , 2019Park et al, 2016). Nonetheless, given the increased fatty acid oxidation observed in mice with knockout of Fyn, another Src kinase family member (Bastie et al, 2007), Src activation by ILTV infection may limit viral intercellular spread by balancing host fatty acid metabolism, which can be negated by Src inhibition, resulting in accelerated viral spread and an exacerbated CPE of infection as observed in our model.…”

Section: Discussionmentioning

confidence: 99%

Host Src controls gallid alpha herpesvirus 1 intercellular spread in a cellular fatty acid metabolism-dependent manner

et al. 2019

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A B S T R A C TViral spread is considered a promising target for antiviral therapeutics, but the associated mechanisms remain unclear for gallid alpha herpesvirus 1 (ILTV). We previously identified proto-oncogene tyrosine-protein kinase Src (Src) as a crucial host determinant of ILTV infection. The present study revealed accelerated spread of ILTV upon Src inhibition. This phenomenon was independent of either viral replication or the proliferation of infected cells and could not be compromised by neutralizing antibody. Neither extracellular vesicles nor the direct cytosol-to-cytosol connections between adjacent cells contributed to the enhanced spread of ILTV upon Src inhibition. Further genome-wide transcriptional profile analyses in combination with functional validation identified fatty acid metabolism as an essential molecular event during modulation of the intercellular spread and subsequent cytopathic effect of ILTV by Src. Overall, these data suggest that Src controls the cell-to-cell spread of ILTV in a cellular fatty acid metabolism-dependent manner, which determines the virus's cytopathic effect.

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Myristoylation of Src kinase mediates Src-induced and high-fat diet–accelerated prostate tumor progression in mice

Cited by 43 publications

References 38 publications

Dietary palmitate cooperates with Src kinase to promote prostate tumor progression

Dietary palmitate cooperates with Src kinase to promote prostate tumor progression

Pharmacologically targeting the myristoylation of the scaffold protein FRS2α inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression

Host Src controls gallid alpha herpesvirus 1 intercellular spread in a cellular fatty acid metabolism-dependent manner

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