Cancer Cell-Derived PDGFB Stimulates mTORC1 Activation in Renal Carcinoma
Asmaa Y Abuhamad1, Nurul Nadia Mohamad Zamberi2, Sakari Vanharanta3,4
1Bionanotechnology Research Group, Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia.
Abstract:
Clear cell renal cell carcinoma (ccRCC) is a hypervascular tumor that is characterized by bi-allelic inactivation of the VHL tumor suppressor gene and mTOR signalling pathway hyperactivation. The pro-angiogenic factor PDGFB, a transcriptional target of super enhancer-driven KLF6, can activate the mTORC1 signalling pathway in ccRCC. However, the detailed mechanisms of PDGFB-mediated mTORC1 activation in ccRCC have remained elusive. Here, we investigated whether ccRCC cells are able to secrete PDGFB into the extracellular milieu and stimulate mTORC1 signalling activity. We found that ccRCC cells secreted PDGFB extracellularly, and by utilizing KLF6- and PDGFB-engineered ccRCC cells, we showed that the level of PDGFB secretion was positively correlated with the expression of intracellular KLF6 and PDGFB. Moreover, the reintroduction of either KLF6 or PDGFB was able to sustain mTORC1 signalling activity in KLF6-targeted ccRCC cells. We further demonstrated that conditioned media of PDGFB-overexpressing ccRCC cells was able to re-activate mTORC1 activity in KLF6-targeted cells. In conclusion, cancer cell-derived PDGFB can mediate mTORC1 signalling pathway activation in ccRCC, further consolidating the link between the KLF6-PDGFB axis and the mTORC1 signalling pathway activity in ccRCC.
Insights
Clear cell renal cell carcinoma (ccRCC) cells secrete PDGFB, activating the mTORC1 pathway. This study reveals the KLF6-PDGFB axis drives ccRCC progression by sustaining mTORC1 signaling.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling
Background:
- Clear cell renal cell carcinoma (ccRCC) is a hypervascular tumor linked to VHL gene inactivation and mTOR pathway hyperactivation.
- Platelet-derived growth factor subunit B (PDGFB), regulated by KLF6, is implicated in activating mTORC1 signaling in ccRCC, but its precise role is unclear.
Purpose of the Study:
- To investigate the secretion of PDGFB by ccRCC cells.
- To determine if secreted PDGFB can activate mTORC1 signaling.
- To elucidate the mechanisms of PDGFB-mediated mTORC1 activation in ccRCC.
Main Methods:
- Engineered ccRCC cells with altered KLF6 and PDGFB expression.
- Assessed PDGFB secretion levels.
- Utilized conditioned media from PDGFB-overexpressing cells to treat KLF6-targeted cells.
- Monitored mTORC1 signaling activity.
Main Results:
- ccRCC cells were confirmed to secrete PDGFB extracellularly.
- Higher PDGFB secretion correlated positively with intracellular KLF6 and PDGFB expression.
- Reintroducing KLF6 or PDGFB restored mTORC1 signaling in targeted ccRCC cells.
- Conditioned media from PDGFB-overexpressing cells reactivated mTORC1 in KLF6-targeted cells.
Conclusions:
- Cancer cell-derived PDGFB plays a key role in activating the mTORC1 signaling pathway in ccRCC.
- This study reinforces the connection between the KLF6-PDGFB axis and mTORC1 pathway activity in ccRCC pathogenesis.
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