Abstract
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.
Highlights
There are very limited treatment options for advanced renal cell carcinoma (RCC)
We have recently reported that the receptor tyrosine kinase, c-Met, which is over-expressed in renal cancer, promotes the survival of renal tumor cells through the regulation of the anti-oxidant cytoprotective molecule heme oxygenase-1 (HO-1); c-Met modulates the expression of the negative co-stimulatory molecule, PD-L1 (Programmed Death-Ligand 1), involved in immune escape of renal cancer cells [14]. c-Met is a known inducer of Ras, which is hyper-active in renal cancer; and Ras has cross-talk with mammalian target of Rapamycin (mTOR)
We show that that the combination treatment with RAPA and Honokiol effectively restricts the growth and cell cycle progression of renal cancer cells by inhibiting the c-Met-HO-1 axis; it down-regulates the expression of PD-L1, which plays a major role in the immune escape of renal cancer cells
Summary
There are very limited treatment options for advanced renal cell carcinoma (RCC). The five-year survival rate for patients with metastatic RCC is less than 10% as the tumors get highly resistant to standard chemo- and radiotherapy [1]. Different therapeutic agents, including, multiple kinase inhibitors (like, sorafenib, sunitinib, cabozantinib and others), mammalian target of Rapamycin (mTOR )inhibitors, and some immune checkpoint inhibitors have been suggested as first-line treatment for advanced RCC, the treatment responses are not long-standing; and the tumors progress due to drug resistance and immune escape [2,3,4]. We identified that CNI can activate the proto-oncogene ras, and promote a rapid progression of renal cancer [13]. We have recently reported that the receptor tyrosine kinase, c-Met (mesenchymal-epithelial transition factor), which is over-expressed in renal cancer, promotes the survival of renal tumor cells through the regulation of the anti-oxidant cytoprotective molecule heme oxygenase-1 (HO-1); c-Met modulates the expression of the negative co-stimulatory molecule, PD-L1 (Programmed Death-Ligand 1), involved in immune escape of renal cancer cells [14]. We have recently reported that the receptor tyrosine kinase, c-Met (mesenchymal-epithelial transition factor), which is over-expressed in renal cancer, promotes the survival of renal tumor cells through the regulation of the anti-oxidant cytoprotective molecule heme oxygenase-1 (HO-1); c-Met modulates the expression of the negative co-stimulatory molecule, PD-L1 (Programmed Death-Ligand 1), involved in immune escape of renal cancer cells [14]. c-Met is a known inducer of Ras, which is hyper-active in renal cancer; and Ras has cross-talk with mTOR
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