Abstract
High-mobility group box 1 (HMGB1) has been found to mediate autophagy during chemotherapy in several cancers. However, whether HMGB1plays a role in autophagy and chemoresistance in bladder cancer is elusive. In this report, HMGB1 expression was found to be increased in 30 primary bladder cancer tissue specimens compared to their matched adjacent non-tumor tissues. While gemcitabine induced apoptotic cell death, it also induced HMGB1 expression and autophagy in bladder cancer T24 and BIU-87 cells. Suppressing HMGB1 expression with siRNA strongly potentiated gemcitabine-induced apoptosis. HMGB1 siRNA or autophagy inhibitors suppressed gemcitabine-induced autophagy. Further, gemcitabine activated c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinase (ERK) and Bcl-2 phosphorylation, and blocking ERK and JNK inhibited autophagy and increased apoptosis in gemcitabine-treated cells. Interestingly, suppressing HMGB1 expression attenuated gemcitabine-induced ERK and JNK activation and Bcl-2 phosphorylation. Thus, our results suggest that while gemcitabine kills bladder cancer cells through apoptosis, a cytoprotective autophagy is also induced involving HMGB1-mediated JNK and ERK to counteract the cytotoxicity of gemcitabine, and intervention targeting this pathway may improve the anticancer efficacy of gemcitabine against bladder cancer.
Highlights
Urinary bladder carcinoma is the fifth most common type of cancer among all cancers and the second most common urologic malignancy [1]
These results suggest High-mobility group box 1 (HMGB1) protein expression is increased and associated with tumor grade and T stage in bladder carcinoma
To investigate the role of HMGB1 in bladder cancer cell’s response to GEM, we examined the effect of HMGB1 knockdown on GEM-induced cytotoxicity (Figure 4A), which was associated with increased apoptosis that was detected as increased caspase-3 and PARP cleavage detected by Western blot and Annexin-V positive staining detected by flow cytometry assay (Figure 4B–4D)
Summary
Urinary bladder carcinoma is the fifth most common type of cancer among all cancers and the second most common urologic malignancy [1]. The majority of bladder cancer patients are diagnosed as the type of nonmuscle invasive tumor that has a high rate of recurrence. Almost one third of these tumors will develop into muscle invasive, metastasis and life-threatening type that requires further treatment [2, 3]. The regimen of gemcitabine (GEM) plus cisplatin is the frontier treatment, because it exerts a clinical efficacy equivalent to that of conventional chemotherapy regimens but has much lower side effects [4]. Gemcitabine, a member of pyrimidine antimetabolite, has been proved to be effective in treating bladder transitional cell carcinoma and other malignancies [5]. The clinical application of gemcitabine is hampered by chemoresistance
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