The mTOR pathway affects proliferation and chemosensitivity of urothelial carcinoma cells and is upregulated in a subset of human bladder cancers

Authors


  • I.M and J.Z. contributed equally to this work

Stephen A. Boorjian, 200 First Street SW, Rochester, MN 55905, USA.
e-mail: sboorjian@gmail.com

Abstract

What’s known on the subject? and What does the study add?

Prior to publication of our paper, evidence had suggested elevated activity of the mTOR pathway in urothelial carcinoma. Separate studies had in addition demonstrated that mTOR inhibition sensitized certain cancer cells to cisplatin therapy. We therefore evaluated the efficacy of mTOR inhibition using in vitro and in vivo models of bladder cancer, and investigated whether mTOR inhibition accentuates the response of bladder cancer cells to cisplatin, which is currently the most effective systemic treatment for metastatic bladder cancer.

We found that mTOR blockade inhibits urothelial carcinoma cell proliferation, and enhances the therapeutic efficacy of cisplatin. Our data support a functional relevance for the mTOR signaling pathway in bladder cancer, and provide evidence to suggest the potential for mTOR inhibitors to be used in combination with cisplatin-based chemotherapy regimens.

OBJECTIVE

• To investigate whether mammalian target of rapamycin (mTOR) inhibition by rapamycin is therapeutically efficacious in combination with cisplatin for bladder cancer.

MATERIALS AND METHODS

• Using a panel of human urothelial carcinoma cell lines, we determined the effect of rapamycin on cell viability, cell-cycle progression, signalling and apoptosis.

• The effect of mTOR inhibition on chemosensitivity was investigated by treating cells with rapamycin, alone, or with cisplatin.

• The effect of rapamycin or cisplatin treatment was assessed in xenograft mice inoculated with urothelial carcinoma cells.

• Expression of p-mTOR in human bladder cancer specimens was assessed using a tissue microarray.

RESULTS

• Treatment with rapamycin significantly decreased cell viability in UMUC3 (P= 0.004) and 253J (P < 0.001) cells. It induced arrest in the G0-G1 phase and decreased activation of p-mTOR and its downstream effector, p-S6K, in both cell lines.

• Treatment with rapamycin increased the ability of cisplatin to inhibit cell viability in UMUC3 (P= 0.002) and 253J (P= 0.03) cells. No evidence for apoptosis induction was noted after treatment with rapamycin alone.

• Mouse xenografts of UMUC3 cells revealed that rapamycin significantly prolonged survival and enhanced the therapeutic efficacy of cisplatin.

• In patient urothelial carcinoma specimens, p-mTOR expression was increased in cancer vs non-tumour bladder tissue in 65/203 (32.0%) tumours.

CONCLUSIONS

• mTOR blockade inhibits urothelial carcinoma cell proliferation and enhances the effectiveness of cisplatin.

• Suppression of the mTOR pathway has the potential to be a therapeutic target in bladder cancer for selected patients.

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