Metformin and pioglitazone are two common oral hypoglycemic agents used to treat diabetes. According to new research, these drugs may contribute to bladder cancer. There is substantial evidence linking diabetes to breast, colon, liver, and pancreatic cancer. The purpose of this study was to look into the molecular mechanisms that underpin the effects of metformin and pioglitazone on bladder epithelial carcinogenesis in type 2 diabetes. Human bladder epithelial cells (HBlEpC) were treated with metformin or pioglitazone in the presence of high glucose and insulin levels. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay and a cell viability and proliferation assay were used to assess cell viability and proliferation. The bromodeoxyuridine incorporation assay was used to examine cell cycle regulatory factors and oncogene expression, while western blotting was used to examine cell cycle regulatory factors and oncogene expression. Metformin and pioglitazone inhibited cell viability in a concentration- and time-dependent manner, which was reversed by high glucose with or without insulin. In HBlEpC co-treated with pioglitazone and metformin, prolonged exposure to high glucose and insulin levels increased cyclin D, cyclin-dependent kinase 4 (Cdk4), and Cdk2 expression while suppressing cyclin-dependent kinase inhibitors p21 and p15/16. Under high stress, the tumor suppressor proteins p53 and cav-1 were downregulated, while the oncogenic protein c-myc was upregulated. Supplementation of glucose and insulin in HBlEpC patients receiving pioglitazone and metformin. In drug-treated cells, prolonged exposure to high glucose with or without insulin decreased the expression of B cell lymphoma 2-associated X (Bax) and failed to increase the expression of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK). These findings imply that hyperglycemic and insulinemic conditions promote cell cycle progression and oncogenic signaling in drug-treated bladder epithelial cells, and that uncontrolled hyperglycemia and hyperinsulinemia are likely to be more cancer risk factors than diabetes drugs. Furthermore, our findings shed light on how these conditions enhance the carcinogenic effect in drug-treated bladder epithelial cells and suggest that uncontrolled hyperglycemia and hyperinsulinemia in diabetics are likely more dangerous than TZD administration or PPAR stimulation in a clinical setting.
Author (S) Details
Daejin Kim
Department of Anatomy, Inje University College of Medicine, Busan 614-735, Republic of Korea.
Byul-Nim Ahn
T2B Infrastructure Center for Ocular Disease, Inje University Busan Paik Hospital, Busan, Republic of Korea.
Yeong Seok Kim
Department of Anatomy, Inje University College of Medicine, Busan 614-735, Republic of Korea.
Dae Young Hur
Department of Anatomy, Inje University College of Medicine, Busan 614-735, Republic of Korea.
Jae Wook Yang
T2B Infrastructure Center for Ocular Disease, Inje University Busan Paik Hospital, Busan, Republic of Korea and Department of Ophthalmology, Inje University College of Medicine, Inje University Busan Paik Hospital, Busan, Republic of Korea.
Ga Bin Park
Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea.
Jung Eun Jang
Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea.
Eun Ju Lee
Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea.
Min Jeong Kwon
Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea.
Tae Nyun Kim
Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea.
Mi Kyung Kim
Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea.
Jeong Hyun Park
Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea.
Byoung Doo Rhee
Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea.
Soon Hee Lee
Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea.
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