Protein Kinase D3 promotes the cell proliferation by activating the ERK1/c‐MYC axis in breast cancer

Abstract

Breast cancer is the second leading death cause of cancer death for all women.Previous study suggested that Protein Kinase D3 (PRKD3) was involved in breast cancer progression. In addition, the protein level of PRKD3 in triple-negative breast adenocarcinoma was higher than that in normal breast tissue. However, the oncogenic mechanisms of PRKD3 in breast cancer is not fully investigated. Multi-omic data showed that ERK1/c-MYC axis was identified as a major pivot in PRKD3-mediated downstream pathways. Our study provided the evidence to support that the PRKD3/ ERK1/c-MYC pathway play an important role in breast cancer progression. We found that knocking out PRKD3 by performing CRISPR/Cas9 genome engineering technology suppressed phosphorylation of both ERK1 and c-MYC but did not down-regulate ERK1/2 expression or phosphorylation of ERK2. The inhibition of ERK1 and c-MYC phosphorylation further led to the lower protein level of c-MYC and then reduced the expression of the c-MYC target genes in breast cancer cells. We also found that loss of PRKD3 reduced the rate of the cell proliferation in vitro and tumour growth in vivo, whereas ectopic (over)expression of PRKD3, ERK1 or c-MYC in the PRKD3knockout breast cells reverse the suppression of the cell proliferation and tumour growth. Collectively, our data strongly suggested that PRKD3 likely promote the cell proliferation in the breast cancer cells by activating ERK1-c-MYC axis. K E Y W O R D Sbreast cancer, c-MYC, ERK1, Protein Kinase D3

The Shuganhuazheng Formula in Triple‐Negative Breast Cancer: A Study Based on Network Pharmacology and In Vivo Experiments

“…As an important member of the Myc family, c-Myc is an oncogene in breast cancer [ 27 ]. It plays an important role in promoting the occurrence and development of tumours [ 28 ] and in promoting and maintaining tumour cell proliferation [ 29 ], differentiation, and apoptosis [ 30 ]. In recent years, a large number of studies have shown that c-Myc plays an important role in regulating the metabolism, proliferation, and apoptosis of TNBC cells [ 30 – 32 ].…”

The oncogenic role of protein kinase D3 in cancer

“…One of the possible mechanisms is that PRKD3 promotes TNBC cell proliferation via contributing to mammalian target of rapamycin complex 1/ribosomal protein S6 kinase B1 pathway activation 29 . Other researchers suggest that PRKD3 promotes the proliferation of breast cancer cells by activating the mitogen-activated protein kinase 3/MYC proto-oncogene axis or ELAV like RNA binding protein 1 32 , 33 . The RhoGEF GRF-H1 is claimed to activate PRKD3 for the maintenance of TNBC stem cells 34 .…”

A phosphoproteomic approach reveals that PKD3 controls phenylalanine and tyrosine metabolism

“…Protein Kinase D (PKD) family members integrate multiple hormonal and metabolic signals to coordinate homeostasis of the organism (Kolczynska, Loza-Valdes et al, 2020, Löffler, Mayer et al, 2018, Rozengurt, 2011, Sumara, Formentini et al, 2009. The family of PKDs comprises three kinases: PKD1, PKD2, and PKD3 (Fu & Rubin, 2011, Rozengurt, 2011.…”

“…PKD1 and PKD2 share the highest homology, while PKD3 kinase is the unique member of the family. PKD1 and PKD2 have been widely studied in different cellular processes such as trans-Golgi network dynamics, cell proliferation and cell migration, adipocytes function, insulin secretion as well as regulation of innate and adaptive immune cells function (Gehart, Goginashvili et al, 2012, Goginashvili, Zhang et al, 2015, Ittner, Block et al, 2012, Kolczynska et al, 2020, Löffler et al, 2018, Rozengurt, 2011, Sumara et al, 2009, Zhang, Meszaros et al, 2017. The specific functions of PKD3 are still relatively unexplored.…”

“…PKD3 also phosphorylates p65 at serine 536, a critical step for the upregulation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and drives glycolysis in gastric cancer cells (Zhang et al, 2019). In addition, gain and loss of function studies suggest that PKD3 regulates the ERK1-MYC axis and promotes cell proliferation in cancer (Chen, Deng et al, 2008, Liu, Song et al, 2019. Finally, in hepatocytes, PKD3 suppresses insulin-dependent AKT and mTORC1/2 activation, which results in peripheral glucose intolerance and suppression of the hepatic lipid production (Mayer et al, 2019).…”