CdGAP promotes prostate cancer metastasis by regulating epithelial-to-mesenchymal transition, cell cycle progression, and apoptosis

Abstract

High mortality of prostate cancer patients is primarily due to metastasis. Understanding the mechanisms controlling metastatic processes remains essential to develop novel therapies designed to prevent the progression from localized disease to metastasis. CdGAP plays important roles in the control of cell adhesion, migration, and proliferation, which are central to cancer progression. Here we show that elevated CdGAP expression is associated with early biochemical recurrence and bone metastasis in prostate cancer patients. Knockdown of CdGAP in metastatic castration-resistant prostate cancer (CRPC) PC-3 and 22Rv1 cells reduces cell motility, invasion, and proliferation while inducing apoptosis in CdGAP-depleted PC-3 cells. Conversely, overexpression of CdGAP in DU-145, 22Rv1, and LNCaP cells increases cell migration and invasion. Using global gene expression approaches, we found that CdGAP regulates the expression of genes involved in epithelial-to-mesenchymal transition, apoptosis and cell cycle progression. Subcutaneous injection of CdGAP-depleted PC-3 cells into mice shows a delayed tumor initiation and attenuated tumor growth. Orthotopic injection of CdGAP-depleted PC-3 cells reduces distant metastasic burden. Collectively, these findings support a pro-oncogenic role of CdGAP in prostate tumorigenesis and unveil CdGAP as a potential biomarker and target for prostate cancer treatments.

CdGAP maintains podocyte function and modulates focal adhesions in a Src kinase-dependent manner

“…Adhesion of foot processes to the GBM via the adhesion molecules such as α3β1-integrins is critical for morphology and function of podocytes 21 . Therefore, of the two GAPs, CdGAP was of particular interest because of its known functions in the regulation of cell migration, adhesion and focal adhesions (FAs) 22 – 25 . Similarly, among the three GEFs, β-PIX is known to modulate FA maturation via Rac1 or Cdc42 26 , and to maintain podocyte architecture and glomerular function 16 .…”

“…FA is an integrin-based multi-protein complex and is essential for podocyte attachment to the GBM and its motility 31 . Pro-migratory and pro-invasive functions were ascribed to CdGAP, which was shown to regulate directional membrane protrusions of migrating osteosarcoma cells 23 , 29 , breast cancer cells 24 , and prostate cancer cells 25 . Consistently, CdGAP KD podocytes showed decreased motility (Fig.…”

“…CdGAP is one of the causative genes associated with Adams-Oliver syndrome, a disorder characterized by scalp defects and terminal transverse limb abnormalities 38 . CdGAP localizes at FAs and participates in the regulation of cell motility and adhesion dynamics 23 , and its roles in cancer cells have been well described 24 , 25 , 29 , 39 . While CdGAP was initially discovered as a GAP for Cdc42, it has been since shown that it acts on both Cdc42 and Rac1 20 , 22 .…”

Astragalus–Scorpion Drug Pair Inhibits the Development of Prostate Cancer by Regulating GDPD4-2/PI3K/AKT/mTOR Pathway and Autophagy

“…20210224026). In this study, 110 male BABL/c nude mice (4–6 weeks) were purchased from Hunan Slacker Jingda Laboratory Animal Co., Ltd. Model construction was described as follows ( Li J. et al, 2020 ; Mehra et al, 2021 ): 2 × 10 6 cells were resuspended in 100 µL serum-free RPMI containing 50% Matrigel (356234, ThermoFisher) and injected subcutaneously into the left side of an athymic mouse. The mice were divided into groups 1 week after injection.…”

CACYBP knockdown inhibits progression of prostate cancer via p53

“…Prostate cancer (PC) is the second most common male genitourinary system tumor with a high incidence, complex and multifocal features and atypical early clinical symptoms (Davidsson et al 2018 ; Mehra et al 2021 ). In addition, PC harbors numerous genetic and epigenetic abnormalities that drive unrestricted cellular growth and increased metabolic demands (Yadav et al 2018 ).…”