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Blockade of the PDGFR family together with SRC leads to diminished proliferation of colorectal cancer cells.


ABSTRACT: Among the family of receptor tyrosine kinases (RTKs), platelet-derived growth factor receptor (PDGFR) has attracted increasing attention as a potential target of anti-tumor therapy in colorectal cancer (CRC). To study the function of PDGFR? in CRC cell lines, SW480, DLD-1 and Caco-2 cells showing high PDGFR? expression were used for receptor down-regulation by small interfering RNA (siRNA) and using the pharmacological inhibitor of PDGFR? Ki11502. Blockade of PDGFR? using both approaches led to moderate inhibition of proliferation and diminished activation of the downstream PI3K-signaling pathway in all three cell lines. Surprisingly, incubation with Ki11502 resulted in an arrest of SW480 cells in the G2 phase of the cell cycle, whereas the siRNA approach did not result in this effect. To address this difference, we analyzed the involvement of the PDGFR? family member c-KIT in Ki11502 effectiveness, but siRNA and proliferation studies in SW480 and DLD-1 cells could not prove the involvement of c-KIT inactivation during Ki11502 treatment. Hence, an RTK activation antibody array on SW480 cells led us to the identification of the non-receptor tyrosine kinase SRC, which is inactivated after Ki11502 treatment but not after the siRNA approach. Further studies using the SRC-specific inhibitor PP2 showed that SRC inhibition upon treatment with the inhibitor Ki11502 is responsible for the observed effects of Ki11502 in SW480 and DLD-1 CRC cells. In summary, our results demonstrate that the inhibition of PDGFR? alone using siRNA has only moderate cellular effects in CRC cell lines; however, the multi-target inhibition of PDGFR?, c-KIT and SRC, e.g., using Ki11502, represents a promising therapeutic intervention for the treatment of CRC.

SUBMITTER: Kaulfuß S 

PROVIDER: S-EPMC3759664 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Blockade of the PDGFR family together with SRC leads to diminished proliferation of colorectal cancer cells.

Kaulfuß Silke S   Seemann Henning H   Kampe Rovena R   Meyer Julia J   Dressel Ralf R   König Britta B   Scharf Jens-Gerd JG   Burfeind Peter P  

Oncotarget 20130701 7


Among the family of receptor tyrosine kinases (RTKs), platelet-derived growth factor receptor (PDGFR) has attracted increasing attention as a potential target of anti-tumor therapy in colorectal cancer (CRC). To study the function of PDGFRβ in CRC cell lines, SW480, DLD-1 and Caco-2 cells showing high PDGFRβ expression were used for receptor down-regulation by small interfering RNA (siRNA) and using the pharmacological inhibitor of PDGFRβ Ki11502. Blockade of PDGFRβ using both approaches led to  ...[more]

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