P2Y2Rmediated transactivation of VEGFR2 through Src phosphorylation is associated with ESM1 overexpression in radiotherapyresistanttriple negative breast cancer cells.
Int J Oncol
; 62(6)2023 Jun.
Article
in En
| MEDLINE
| ID: mdl-37165911
ABSTRACT
We previously reported that radiotherapyresistant (RTR) triple negative breast cancer (TNBC) cells upregulate the expression of endothelialspecific molecule1 (ESM1) compared with TNBC cells. In addition, ESM1 is involved in an increased proliferation and invasion of RTRTNBC cells compared with TNBC cells. It was further identified that, in RTRTNBC cells, P2Y2 purinergic receptor (P2Y2R)mediated activation of p21activated kinase 1 (PAK1), protein kinase C (PKC), cJun Nterminal kinase (JNK) and p38 MAPKs is related to ESM1 expression via forkhead box O1 (FoxO1) regulation. Notably, it has been reported that P2Y2R mediates the transactivation of vascular epithelial growth factor receptor 2 (VEGFR2), and VEGFR2 is known to be involved in ESM1 expression. Therefore, in the present study, the involvement of VEGFR2 in the P2Y2Rmediated ESM1 upregulation in RTRTNBC cells and the relationship between P2Y2R and VEGFR2 activation was further examined. Western blotting and reverse transcriptionPCR were used to monitor the expression of ESM1, and the results demonstrated that extracellular ATP treatment regulated the expression of ESM1 in a P2Y2Rdependent manner in RTRMDAMB231 cells. In addition, extracellular ATP activated Src and VEGFR2 after 5 min of incubation, which was abolished by knockdown of P2Y2R expression. VEGFR2 activation in response to ATP was also decreased by inhibiting Src activity, suggesting that ATPactivated P2Y2R regulates VEGFR2 phosphorylation via Src activation. Furthermore, ATPinduced ESM1 expression was decreased by transfection with VEGFR2 small interfering RNA (siRNA). ESM1related signaling molecules, PAK1, PKC, JNK and p38 MAPKs, and the transcriptional regulator, FoxO1, which were activated by ATP, were also decreased following transfection with VEGFR2 siRNA. These results suggest that P2Y2Rmediated transactivation of VEGFR2 through Src phosphorylation is associated with ESM1 overexpression in RTRTNBC cells.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Vascular Endothelial Growth Factor Receptor-2
/
Receptors, Purinergic P2Y2
/
Triple Negative Breast Neoplasms
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Int J Oncol
Journal subject:
NEOPLASIAS
Year:
2023
Document type:
Article