Abstract
Colorectal cancer (CRC) is often resistant to conventional therapies. Previous studies have reported the anticancer effects of vitamin D in several cancers, its role in radiotherapy (RT) remains unknown. We found that 1α, 25-dihydroxyvitamin D3 (VD3), the biologically active form of vitamin D, had antitumor effect on CRC and sensitized CRC cells to ionizing radiation (IR). VD3 demonstrated synergistic effect in combination with IR, which were detected by colony formation and cell proliferation assay. Radiosensitivity restoration induced by VD3 was associated with a series of phenotypes, including apoptosis, autophagy, and epithelial-mesenchymal transition (EMT). Using proteomics, “regulation of cell migration” and “cadherin” were found to be obviously enriched GO terms. Moreover, cystatin D and plasminogen activator inhibitor-1 (PAI-1), the differentially expressed proteins, were associated with EMT. Next, we confirmed the contributions of these two genes in enhancing IR sensitivity of CRC cells upon inhibition of EMT. As determined by proteomics, the mechanism underlying such sensitivity involved partially block of JAK/STAT3 signaling pathway. Furthermore, VD3 also elicited sensitization to RT in xenograft CRC models without additional toxicity. Our study revealed that VD3 was able to act in synergy with IR both in vitro and in vivo and could also confer radiosensitivity by regulating EMT, thereby providing a novel insight for elevating the efficacy of therapeutic regimens.
Highlights
Colorectal cancer (CRC) is reported to be the second and third most common cancer in women and men, respectively, with a high incidence and mortality (Dekker et al, 2019)
Given that vitamin D plays an essential role in induction of apoptosis (Polar et al, 2003; DeMasters et al, 2004), we performed apoptosis assay and found that there were more apoptotic cells with combined treatment compared to ionizing radiation (IR) alone (Figure 1E)
Our study showed that the treatment with vitamin D restored sensitivity to IR validated by various phenotypes
Summary
Colorectal cancer (CRC) is reported to be the second and third most common cancer in women and men, respectively, with a high incidence and mortality (Dekker et al, 2019). The overall prognosis of advanced CRC remains dismal. Radiotherapy (RT) plays a significant role in the survival of CRC patients. Intrinsic and acquired radioresistance are the major causes of subsequent tumor recurrence and metastasis. Previous studies have reported various types of cell death involved in radiation-induced resistance (Kim et al, 2015). Elucidating the molecular mechanisms underlying such resistance and discovering potential sensitizers will aid in promoting therapeutic efficiency
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