Miconazole induces protective autophagy in bladder cancer cells
Chao-Yen Ho1,2, An-Chen Chang3, Chung-Hua Hsu2
1Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
Abstract:
Autophagy plays a dual function in cancer progression; autophagy activation can support cancer cell survival or contribute to cell death. Miconazole, a Food and Drug Administration-approved antifungal drug, has been implicated in oncology research recently. Miconazole was found to exert antitumor effects in various tumors, including bladder cancer (BC). However, whether it provokes protective autophagy has been never discussed. We provide evidence that miconazole induces protective autophagy in BC for the first time. The results indicated that 1A/1B-light chain 3 (LC3)-II processing and p62 expression were elevated after miconazole exposure. Also, adenosine monophosphate-activated protein kinase phosphorylation was increased after miconazole treatment. We also confirmed the autophagy-promoting effect of miconazole in the presence of bafilomycin A1 (Baf A1). The result indicates that a combination treatment of miconazole and Baf A1 improved LC3-II processing, confirming that miconazole promoted autophagic flux. The acridine orange, Lysotracker, and cathepsin D staining results indicate that miconazole increased lysosome formation, revealing its autophagy-promoting function. Finally, miconazole and autophagy inhibitor 3-methyladenine cotreatment further reduced the cell viability and induced apoptosis in BC cells, proving that miconazole provokes protective autophagy in BC cells. Our findings approve that miconazole has an antitumor effect in promoting cell apoptosis; however, its function of protective autophagy is needed to be concerned in cancer treatment.
Insights
Miconazole, an antifungal drug, triggers protective autophagy in bladder cancer (BC) cells. This autophagy promotes cell survival, but combining miconazole with autophagy inhibitors enhances its antitumor effects by inducing apoptosis.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Autophagy has a dual role in cancer, potentially supporting cancer cell survival or inducing cell death.
- Miconazole, an antifungal agent, shows promise as an anticancer drug, particularly in bladder cancer (BC).
- The specific role of miconazole in inducing autophagy in BC remains unexplored.
Purpose of the Study:
- To investigate whether miconazole induces protective autophagy in bladder cancer cells.
- To elucidate the mechanism by which miconazole affects autophagy.
- To evaluate the combined effect of miconazole and autophagy inhibition on BC cell viability and apoptosis.
Main Methods:
- Assessed autophagy markers, including microtubule-associated protein 1A/1B-light chain 3 (LC3)-II processing and p62 expression.
- Measured adenosine monophosphate-activated protein kinase (AMPK) phosphorylation.
- Evaluated autophagic flux using bafilomycin A1 (Baf A1) and assessed lysosome formation via acridine orange, Lysotracker, and cathepsin D staining.
- Determined the impact of miconazole combined with autophagy inhibitor 3-methyladenine on cell viability and apoptosis.
Main Results:
- Miconazole exposure increased LC3-II processing and p62 levels, indicating autophagy induction.
- Miconazole treatment elevated AMPK phosphorylation and enhanced autophagic flux and lysosome formation.
- Combined treatment with miconazole and 3-methyladenine significantly reduced cell viability and increased apoptosis in BC cells.
Conclusions:
- Miconazole induces protective autophagy in bladder cancer cells.
- The findings demonstrate miconazole's antitumor potential through apoptosis induction.
- The protective role of autophagy in response to miconazole warrants consideration for optimizing cancer treatment strategies.
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