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A Novel Combination Treatment with Honokiol and Rapamycin Effectively Restricts c-Met-Induced Growth of Renal Cancer Cells, and also Inhibits the Expression of Tumor Cell PD-L1 Involved in Immune Escape

1
Division of Nephrology, Boston Children’s Hospital, Boston, MA 02115, USA
2
Harvard Medical School, Boston, MA 02115, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(7), 1782; https://doi.org/10.3390/cancers12071782
Received: 16 June 2020 / Revised: 30 June 2020 / Accepted: 1 July 2020 / Published: 3 July 2020
The mTOR inhibitor Rapamycin has tumor inhibitory properties; and it is also used as an immunosuppressive agent after organ transplantation. However, prolonged Rapamycin treatment re-activates Akt and can promote cancer growth. Honokiol is a natural compound with both anti-tumorigenic and anti-inflammatory properties. Here, we assessed the anti-tumor effects of Rapamycin and Honokiol combination in renal cell carcinoma (RCC). Receptor tyrosine kinase c-Met-mediated signaling plays a major role in RCC growth. We observed that compared with Rapamycin alone, Rapamycin + Honokiol combination can effectively down-regulate c-Met-induced Akt phosphorylation in renal cancer cells; and it markedly inhibited Ras activation and cell proliferation and promoted G1 phase cell cycle arrest. The combination treatment significantly induced ROS generation and cancer cell apoptosis even when c-Met is activated. Importantly, Honokiol, but not Rapamycin, decreased c-Met-induced expression of the co-inhibitory molecule PD-L1, implied in the immune escape of renal cancer cells. In mouse renal cancer cells and Balb/c splenocytes co-culture assay, Rapamycin + Honokiol markedly potentiated immune-cell-mediated killing of cancer cells, possibly through the down-regulation of PD-L1. Together, Honokiol can effectively overcome the limitation of Rapamycin treatment alone; and the combination treatment can markedly restrict the growth of RCC, with particular importance to post-transplantation renal cancer. View Full-Text
Keywords: receptor tyrosine kinase; renal cell carcinoma; c-Met; Honokiol; mTOR inhibitor; PD-L1 receptor tyrosine kinase; renal cell carcinoma; c-Met; Honokiol; mTOR inhibitor; PD-L1
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MDPI and ACS Style

Sabarwal, A.; Chakraborty, S.; Mahanta, S.; Banerjee, S.; Balan, M.; Pal, S. A Novel Combination Treatment with Honokiol and Rapamycin Effectively Restricts c-Met-Induced Growth of Renal Cancer Cells, and also Inhibits the Expression of Tumor Cell PD-L1 Involved in Immune Escape. Cancers 2020, 12, 1782. https://doi.org/10.3390/cancers12071782

AMA Style

Sabarwal A, Chakraborty S, Mahanta S, Banerjee S, Balan M, Pal S. A Novel Combination Treatment with Honokiol and Rapamycin Effectively Restricts c-Met-Induced Growth of Renal Cancer Cells, and also Inhibits the Expression of Tumor Cell PD-L1 Involved in Immune Escape. Cancers. 2020; 12(7):1782. https://doi.org/10.3390/cancers12071782

Chicago/Turabian Style

Sabarwal, Akash; Chakraborty, Samik; Mahanta, Simran; Banerjee, Selina; Balan, Murugabaskar; Pal, Soumitro. 2020. "A Novel Combination Treatment with Honokiol and Rapamycin Effectively Restricts c-Met-Induced Growth of Renal Cancer Cells, and also Inhibits the Expression of Tumor Cell PD-L1 Involved in Immune Escape" Cancers 12, no. 7: 1782. https://doi.org/10.3390/cancers12071782

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