RAB3D, upregulated by aryl hydrocarbon receptor (AhR), promotes the progression of prostate cancer by activating the PI3K/AKT signaling pathway

Abstract

Many patients with prostate cancer (PCa) cannot be diagnosed until an advanced stage, which make PCa become a large threat to human health. It is an urgent need to explore novel biomarkers for accurate diagnosis and targets for the effective treatment of PCa. This study aimed to investigate the effects of RAB3D (which belongs to the secretory Rab GTPases) on the progression of PCa. The results showed that RAB3D was highly expressed in PCa tissues compared to normal tissues according to the gene expression omnibus dataset. Consistent with the bioinformatics results, RAB3D exhibited a higher expression in PCa cells. Overexpression of RAB3D promoted the proliferation, migration, and invasion of PCa cells, whereas the knockdown of RAB3D led to the opposite results. The procancer effects of RAB3D were further confirmed by the in vivo growth of xenograft model. Subsequently, RAB3D upregulated the PI3K/AKT signaling pathway both in vivo and in vitro. LY294002 (a PI3K inhibitor) rescued the RAB3D upregulation-induced promotion of malignant phenotypes of PCa cells. Furthermore, the transcription activity of RAB3D was found to be enhanced by aryl hydrocarbon receptor (AhR; a transcription factor). The AhR silencing-induced inhibition of the proliferation and migration of PCa cells was reversed by the overexpression of RAB3D. Taken together, RAB3D, upregulated by AhR, promotes the PCa progression by activating the PI3K/AKT signaling pathway.

The Molecular Biology of Prostate Cancer Stem Cells: From the Past to the Future

“…Mechanistically, the enrichment of the PCSC population was at least partially due to AKT-mediated nuclear export and degradation of FOXO3a, one critical transcription factor regulating the stemness of CSCs. Additional evidence suggested that the inhibition of PI3K/AKT signaling by LY294002 and NVP-BEZ235 indeed noticeably suppressed the survival and sphere forming ability of PCa cells [147,148]. In agreement with this finding, L Chang and his colleagues also elucidated that the PI3K/AKT regulated stemness phenotype was causally associated with the radio-resistance of PCa [149].…”

Network pharmacology and experimental evaluation strategies to decipher the underlying pharmacological mechanism of Traditional Chinese Medicine CFF-1 against prostate cancer

“…The PI3K/Akt signaling pathway, a vital intracellular pathway, involved in tumor progression of various malignant tumors [ 15 ]. This pathway emerges as a central oncogenic axis in PCa, orchestrating a spectrum of cellular activities including proliferation, apoptosis, cell cycling, metastasis, and drug resistance [ 16 – 20 ]. The modulation of PI3K/Akt by CFF-1, as evidenced in our findings, could thus represent a significant stride in targeting these fundamental oncological processes.…”

“…The PI3K/Akt signaling pathway, a vital intracellular pathway, involved in tumor progression of various malignant tumors [15]. This pathway emerges as a central oncogenic axis in PCa, orchestrating a spectrum of cellular activities including proliferation, apoptosis, cell cycling, metastasis, and drug resistance [16][17][18][19][20].…”