Open AccessDown‐regulation of PKM 2 enhances anticancer efficiency of THP on bladder cancer
Author(s) -
Su Qiongli,
Tao Ting,
Tang Lei,
Deng Jun,
Darko Kwame Oteng,
Zhou Sichun,
Peng Mei,
He Shanping,
Zeng Qing,
Chen Alex F.,
Yang Xiaoping
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13571
Subject(s) - bladder cancer , in vivo , ampk , cancer research , cancer cell , cancer , medicine , pharmacology , chemistry , kinase , protein kinase a , biology , biochemistry , microbiology and biotechnology
Pyruvate kinase M2 ( PKM 2) regulates the final step of glycolysis levels that are correlated with the sensitivity of anticancer chemotherapeutic drugs. THP is one of the major drugs used in non‐muscle‐invasive bladder cancer instillation chemotherapy. However, low response ratio of THP (19.7%) treatment to human genitourinary tumours using collagen gel matrix has been observed. This study aims to investigate the effect of down‐regulation of PKM 2 on THP efficiency. Via inhibitor or si RNA , the effects of reduced PKM 2 on the efficiency of THP were determined in 2 human and 1 murine bladder cancer cell lines, using MTT , cologenic and fluorescence approaches. Molecular mechanisms of PKM 2 on THP sensitization were explored by probing p‐ AMPK and p‐ STAT 3 levels via WB . Syngeneic orthotopic bladder tumour model was applied to evaluate this efficiency in vivo, analysed by Kaplan‐Meier survival curves, body and bladder weights plus immunohistochemistric tumour biomarkers. PKM 2 was overexpressed in bladder cancer cells and tissues, and down‐regulation of PKM 2 enhanced the sensitivity of THP in vitro. Activation of AMPK is essential for THP to exert anti‐bladder cancer activities. On the other hand, down‐regulating PKM 2 activates AMPK and inhibits STAT 3, correlated with THP sensitivity. Compared with THP alone (400 μmol L −1 , 50 μL), the combination with metformin (60 mmol L −1 , 50 μL) stopped growth of bladder cancer completely in vivo (combination group VS normal group P = .078). Down‐regulating the expression of PKM 2 enhances the anticancer efficiency of THP . This study provides a new insight for improving the chemotherapeutic effect of THP .