Abstract
BackgroundVitamin D3 (VitD) deficiency is linked to increased incidence and worse survival in bladder cancer (BCa). In addition to cystectomy, patients are treated with cisplatin‐based chemotherapy, however 30%‐50% of patients do not benefit from this treatment. The effects of VitD deficiency on response to chemotherapy remain unknown.MethodsTo test effects of VitD supplementation on the response to cisplatin we analyzed patient serum VitD levels and correlated that with survival. In vivo, VitD deficient mice were treated with cisplatin, with or without pretreatment with the active VitD metabolite, 1,25 dihydroxyvitamin D3 (1,25D3). Lastly, using BCa cell lines, T24 and RT‐112, the mechanism of action of 1,25D3 and cisplatin combination treatment was determined by apoptosis assays, as well as western blot and RT‐PCR.ResultsIn this study, we determined that low serum 25 hydroxyvitamin D3 (25D3) levels was significantly associated with worse response to cisplatin. Pretreating deficient mice with 1,25D3, reduced tumor volume compared to cisplatin monotherapy. In vitro, 1,25D3 pretreatment increased the apoptotic response to cisplatin. 1,25D3 pretreatment increased expression of TAp73 and its pro‐apoptotic targets, in a VDR dependent manner. VDR and its transcriptional targets were induced after 1,25D3 treatment and further increased after the combination of 1,25D3 and cisplatin in a TAp73 dependent manner.ConclusionsOur data suggest that VitD deficiency could be a biomarker for poor response to cisplatin, and pretreating with VitD can increase the apoptotic response to cisplatin through VDR and TAp73 signaling crosstalk.
Highlights
Bladder cancer (BCa) is the seventh most common cancer in the US, with 81 000 new cases and 17 000 deaths in 2018.1Muscle invasive bladder cancer (MIBC) has worse survival, is more likely to become metastatic, and is treated with multi‐agent cisplatin‐based neoadjuvant chemotherapy and radical cystectomy.[2]
The ratio of TAp73/ΔNp73 increases approximately 3‐fold after the combination treatment in both cell lines (Figure 5C, *P < 0.05, **P < 0.01). These results suggest that the increase in apoptosis seen after 1,25 hydroxyvitamin D3 (25D3) pretreatment may be in part due to the increased transcription of TAp73 over ΔNp73. mRNA levels of transcriptional targets of TAp73, BAX and NOXA, and protein levels of BAX were found to increase after the combination treatment
30%‐50% of BCa patients treated with cisplatin‐based chemotherapy will not benefit from therapy and 50% of patients treated with cystectomy develop metastatic disease within 2 years.[3,4,5,31,33]
Summary
This work was supported by National Cancer Institute grants CA067267 (CSJ) and CA016056 (CSJ) and Mark Diamond Research Fund (University at Buffalo) grant SP‐16‐06 (Bunch). This work was also supported by the Intramural Research Program of the National Institutes of Health, National Institute on Minority Health and Health Disparities.
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