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Oncogenesis. 2019 Jan 15;8(2):7. doi: 10.1038/s41389-018-0116-9.

Activation of c-Met in cancer cells mediates growth-promoting signals against oxidative stress through Nrf2-HO-1.

Author information

1
Division of Nephrology, Boston Children's Hospital, Boston, MA, 02115, USA.
2
Harvard Medical School, Boston, MA, 02115, USA.
3
Department of Anesthesiology, Boston Children's Hospital, Boston, MA, 02115, USA.
4
Dana Farber Cancer Institute, Boston, MA, 02115, USA.
5
Division of Nephrology, Boston Children's Hospital, Boston, MA, 02115, USA. soumitro.pal@childrens.harvard.edu.
6
Harvard Medical School, Boston, MA, 02115, USA. soumitro.pal@childrens.harvard.edu.

Abstract

Any imbalance between reactive oxygen species (ROS) generation and the anti-oxidant capacity lead to cellular oxidative stress. Many chemotherapeutic agents mediate their cytotoxic functions through the generation of ROS. c-Met, a receptor tyrosine kinase, is over-expressed in renal cancer and plays very crucial role(s) in its growth and survival. Here, we show that c-Met activation protected renal cancer cells from ROS, oxidative stress and cytotoxicity induced by the anti-cancer agent sorafenib (used for renal cancer treatment); and it markedly attenuated sorafenib-induced DNA damage. Activated c-Met promoted the anti-apoptotic proteins (Bcl-2 and Bcl-xL) and inhibited apoptotic cleaved caspase-3. We found that the cytoprotective function of c-Met against sorafenib-induced ROS generation and apoptosis was mediated primarily through the activation of anti-oxidant Nrf2-HO-1. c-Met promoted the nuclear localization of Nrf2 and hindered its binding with the inhibitory protein Keap1. Silencing of Nrf2 attenuated the protective action of c-Met against sorafenib-induced oxidative stress. To evaluate the physiological significance of our findings, in a tumor xenograft model, we observed that a combination treatment with pharmacological inhibitors of c-Met and it's anti-oxidant downstream effecter HO-1 markedly reduced the growth of renal tumor in vivo; it increased the oxidative stress, DNA damage and apoptotic markers in the tumor xenografts, along with reduced tumor vessel density. Our observations indicate that the c-Met-Nrf2-HO-1 pathway plays a vital role in relieving ROS-mediated oxidative stress of renal tumors. Targeting this pathway can significantly increase the oxidative stress to promote apoptotic death of cancer cells.

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