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J Cell Biochem. 2018 Jun;119(6):4592-4606. doi: 10.1002/jcb.26616. Epub 2018 Feb 27.

Ganoderma microsporum immunomodulatory protein induces apoptosis and potentiates mitomycin C-induced apoptosis in urinary bladder urothelial carcinoma cells.

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Proteomics Laboratory, Department of Medical Research, Cathay General Hospital, Taipei, Taiwan.
School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan.
Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
Clinical Gene Laboratory, Department of Medical Research, Cathay General Hospital, Taipei, Taiwan.
Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
Department of Urology, Sijhih Cathay General Hospital, New Taipei City, Taiwan.
College of Nursing and Health Science, Da-Yeh University, Changhua, Taiwan.
Department of Surgery, Cathay General Hospital, Taipei, Taiwan.
Department of Orthopedics, Cathay General Hospital, Taipei, Taiwan.
Department of Biomedical Sciences and Engineering, National Central University, Jhongli, Taiwan.
Center for Biocellular Engineering, National Central University, Jhongli, Taiwan.


Current chemotherapy and immunotherapy treatments followed by transurethral resection for urinary bladder urothelial carcinoma (UC) usually suffer from poor prognosis and high recurrence rate. Design and modification of current formulation with the novel adjuvants are needed. A recombinant protein derived from Ganoderma microsporum named as Ganoderma microsporum immunomodulatory protein (GMIP) was used to treat UC cells. We found GMIP elicits a dose-dependent and time-dependent anti-UC cell proliferation effect, with a half-maximal inhibition concentration (IC50 ) comparable to mitomycin C (MMC), a commonly used chemotherapy agent. After GMIP treatment, UC cells showed apoptotic phenomenon including cell cycle arrest in the G1 phase, elevated sub-G1 population, mitochondrial membrane potential loss, up-regulated p21 expression, p21 nuclear translocation, caspase activation, and PARP cleavage in a p53-independent but p21-mediated pathways. Unlike lung cancer cells, GMIP treated UC cells showed no autophagic scheme including Beclin-1, an autophagy to apoptosis switch marker, was not cleaved by caspase 3 and slight LC3B-II accumulation. Also, the classic autophagic inhibitor, chloroquine had no effect in GMIP-mediated cell death made us conclude that GMIP induced apoptosis through caspase activation but not autophagy in UC cells. Additionally, GMIP showed synergistic effects with MMC in killing UC cells and thus decreased the concentration of MMC usage to reach the comparable apoptotic effects. Our results delineate novel strategies for treatment of UC by GMIP alone or in combination with MMC application and provide a promising therapeutic cocktail for better treatment of urinary bladder urothelial carcinoma.


apoptosis; bladder urothelial carcinoma; ganoderma microsporum immunomodulatory protein; mitomycin C


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