Anti-Metastatic Effect of Pyruvate Dehydrogenase Kinase 4 Inhibition in Bladder Cancer via the ERK, SRC, and JNK Pathways

Eun Hye Lee; Jae-Wook Chung; Eunji Sung; Bo Hyun Yoon; Minji Jeon; Song Park; So Young Chun; Jun Nyung Lee; Bum Soo Kim; Hyun Tae Kim; Tae Hwan Kim; Seock Hwan Choi; Eun Sang Yoo; Tae Gyun Kwon; Ho Won Kang; Wun-Jae Kim; Seok Joong Yun; Sangkyu Lee; Yun-Sok Ha

doi:10.3390/ijms232113240

Anti-Metastatic Effect of Pyruvate Dehydrogenase Kinase 4 Inhibition in Bladder Cancer via the ERK, SRC, and JNK Pathways

Int J Mol Sci. 2022 Oct 31;23(21):13240. doi: 10.3390/ijms232113240.

Authors

Eun Hye Lee¹, Jae-Wook Chung², Eunji Sung³, Bo Hyun Yoon¹, Minji Jeon¹, Song Park⁴, So Young Chun⁵, Jun Nyung Lee², Bum Soo Kim², Hyun Tae Kim², Tae Hwan Kim², Seock Hwan Choi², Eun Sang Yoo², Tae Gyun Kwon², Ho Won Kang^{6

7}, Wun-Jae Kim^{6

8}, Seok Joong Yun^{6

7}, Sangkyu Lee³, Yun-Sok Ha²

Affiliations

¹ Joint Institute of Regenerative Medicine, Kyungpook National University, Daegu 41566, Korea.
² Department of Urology, School of Medicine, Kyungpook National University, Daegu 41405, Korea.
³ BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.
⁴ Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Korea.
⁵ BioMedical Research Institute, Kyungpook National University Hospital, Daegu 41944, Korea.
⁶ Department of Urology, College of Medicine, Chungbuk National University, Cheongju 28644, Korea.
⁷ Department of Urology, Chungbuk National University Hospital, Cheongju 28644, Korea.
⁸ Institute of Urotech, Cheongju 28120, Korea.

Abstract

Bladder cancer is a common global cancer with a high percentage of metastases and high mortality rate. Thus, it is necessary to identify new biomarkers that can be helpful in diagnosis. Pyruvate dehydrogenase kinase 4 (PDK4) belongs to the PDK family and plays an important role in glucose utilization in living organisms. In the present study, we evaluated the role of PDK4 in bladder cancer and its related protein changes. First, we observed elevated PDK4 expression in high-grade bladder cancers. To screen for changes in PDK4-related proteins in bladder cancer, we performed a comparative proteomic analysis using PDK4 knockdown cells. In bladder cancer cell lines, PDK4 silencing resulted in a lower rate of cell migration and invasion. In addition, a PDK4 knockdown xenograft model showed reduced bladder cancer growth in nude mice. Based on our results, PDK4 plays a critical role in the metastasis and growth of bladder cancer cells through changes in ERK, SRC, and JNK.

Keywords: bladder cancer; invasion; metastasis; muscle-invasive bladder cancer (MIBC); pyruvate dehydrogenase kinase 4 (PDK4).

MeSH terms

Animals
Humans
MAP Kinase Signaling System / drug effects
Mice
Mice, Nude
Protein Kinase Inhibitors* / pharmacology
Protein Kinase Inhibitors* / therapeutic use
Protein Serine-Threonine Kinases / antagonists & inhibitors
Proteomics
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Urinary Bladder Neoplasms* / drug therapy
Urinary Bladder Neoplasms* / metabolism
src-Family Kinases / drug effects
src-Family Kinases / metabolism

Substances

Protein Serine-Threonine Kinases
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
pyruvate dehydrogenase kinase 4
Protein Kinase Inhibitors
src-Family Kinases

Grants and funding

2019R1A2C1004046, 2020R1A2B5B03002344, 2020R1I1A3071568, 2021R1G1A1092985, and 2022R1I1A3069482/National Research Foundation of Korea (NRF) funded by the Korean government (MSIT)