Abstract
ABSTRACTPirarubicin (THP) is a newer generation anthracycline anticancer drug. In the clinic, THP and THP-based combination therapies have been demonstrated to be effective against various tumors without severe side effects. However, previous clinical studies have shown that most patients with cervical cancer are not sensitive to THP treatment, and the associated mechanisms are not clear. Consistent with the clinical study, we confirmed that cervical cancer cells were resistant to THP in vitro and in vivo. Our data demonstrated that THP induced a protective macroautophagy/autophagy response in cervical cancer cells, and suppression of this autophagy dramatically enhanced the cytotoxicity of THP. By scanning the mRNA level change of autophagy-related genes, we found that the upregulation of ATG4B (autophagy-related 4B cysteine peptidase) plays an important role in THP-induced autophagy. Moreover, THP increased the mRNA level of ATG4B in cervical cancer cells by promoting mRNA stability without influencing its transcription. Furthermore, THP triggered a downregulation of MIR34C-5p, which was associated with the upregulation of ATG4B and autophagy induction. Overexpression of MIR34C-5p significantly decreased the level of ATG4B and attenuated autophagy, accompanied by enhanced cell death and apoptosis in THP-treated cervical cancer cells. These results for the first time reveal the presence of a MIR34C-5p-ATG4B-autophagy signaling axis in THP-treated cervical cancer cells in vitro and in vivo, and the axis, at least partially, accounts for the THP nonsensitivity in cervical cancer patients. This study may provide a new insight for improving the chemotherapeutic effect of THP, which may be beneficial to the further clinical application of THP in cervical cancer treatment.
Highlights
Pirarubicin (THP, C32H37NO12), a derivative of doxorubicin, is an anthracycline drug that is widely used to treat hematological malignancies in the clinic.[1]
The inhibitor of MIR34C-5p could increase the luciferase activity of pmir-ATG4B by repressing endogenous MIR34C-5p (Fig. S4). These results indicate that the 265–272 region in the 30-UTR of ATG4B mRNA is the binding site of MIR34C-5p, which plays an important role in the regulation of ATG4B mRNA stability
To the best of our knowledge, this study presents the first evidence that THP induced protective autophagy through a MIR34C-5p-ATG4B pathway in cervical cancer cells
Summary
Pirarubicin (THP, C32H37NO12), a derivative of doxorubicin, is an anthracycline drug that is widely used to treat hematological malignancies in the clinic.[1] Studies have confirmed the effectiveness of THP in bladder cancer,[2] ovarian cancer[3] and breast cancer[4] in vitro. Increasing evidence has confirmed the importance of autophagy in determining the response of tumor cells to anticancer therapy.[8,9] Recent studies have shown that THP, with its prodrug, induces a cytoprotective autophagy response in bladder cancer,[10] acute myeloid leukemia[11] and breast cancer.[12] it is still unknown whether this protective antophagy contributes to the nonsensitivity of THP in cervical cancer cells
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