PDK1- and PDK2-mediated metabolic reprogramming contributes to the TGFβ1-promoted stem-like properties in head and neck cancer

Wan-Hsuan Sun; Yun-Hsuan Chen; Hou-Hsuan Lee; Yu-Wen Tang; Kuang-Hui Sun

doi:10.1186/s40170-022-00300-0

PDK1- and PDK2-mediated metabolic reprogramming contributes to the TGFβ1-promoted stem-like properties in head and neck cancer

Cancer Metab. 2022 Dec 6;10(1):23. doi: 10.1186/s40170-022-00300-0.

Authors

Wan-Hsuan Sun¹, Yun-Hsuan Chen², Hou-Hsuan Lee², Yu-Wen Tang³, Kuang-Hui Sun^{4

5}

Affiliations

¹ Division of Head & Neck Surgery, Department of Otolaryngology, Tri-Service General Hospital and National Defense Medical Center, Taipei, 112, Taiwan, Republic of China.
² Department of Biotechnology and Laboratory Science in Medicine, Cancer Progression Research Center, National Yang Ming Chiao Tung University, #155, Section 2, Lie-Nong Street, Taipei, 112, Taiwan, Republic of China.
³ Division of Oral & Maxillofacial Surgery, Department of Stomatology, Taichung Veterans General Hospital, Taichung, 407, Taiwan, Republic of China.
⁴ Department of Biotechnology and Laboratory Science in Medicine, Cancer Progression Research Center, National Yang Ming Chiao Tung University, #155, Section 2, Lie-Nong Street, Taipei, 112, Taiwan, Republic of China. khsun@nycu.edu.tw.
⁵ Department of Education and Research, Taipei City Hospital, Taipei, 112, Taiwan, Republic of China. khsun@nycu.edu.tw.

Abstract

Background: Resistance to chemotherapeutic drugs is a key factor for cancer recurrence and metastases in head and neck cancer (HNC). Cancer stem cells (CSCs) in tumors have self-renewal, differentiation, and higher drug resistance capabilities, resulting in a poor prognosis for patients. In glucose metabolism, pyruvate dehydrogenase kinase (PDK) inhibits pyruvate dehydrogenase and impedes pyruvate from being metabolized into acetyl-CoA and entering the tricarboxylic acid cycle to generate energy. Studies have reported that PDK1 and PDK2 inhibition suppresses the growth, motility, and drug resistance of cancer cells. Furthermore, while TGFβ1 levels are persistently elevated in HNC patients with poor prognosis, the role of PDK isoforms in the TGFβ1-promoted progression and stem-like properties of HNC is unclear.

Methods: Levels of PDK1 and PDK2 were evaluated in HNC tissue microarrays by immunohistochemistry to explore potential clinical relevance. PDK1 and PDK2 were knocked down by the lentivirus shRNA system to investigate their role in TGFβ1-promoted tumor progression in vitro.

Results: We found that PDK2 levels were increased in the later stage of HNC tissues compared to constant PDK1 expression. After PDK1 and PDK2 knockdown, we discovered increased ATP production and decreased lactate production in TGFβ1-treated and untreated HNC cells. However, only PDK2 silencing significantly inhibited the clonogenic ability of HNC cells. We subsequently found that TGFβ1-promoted migration and invasion capabilities were decreased in PDK1 and PDK2 knockdown cells. The tumor spheroid-forming capability, motility, CSC genes, and multidrug-resistant genes were downregulated in PDK1 and PDK2 silencing CSCs. PDK1 and PDK2 inhibition reversed cisplatin and gemcitabine resistance of CSCs, but not paclitaxel resistance.

Conclusion: The results demonstrated that the PDK1- and PDK2-mediated Warburg effect contributes to the TGFβ1-enhanced stemness properties of HNC. Therefore, PDK1 and PDK2 may serve as molecular targets for the combination therapy of HNC.

Keywords: Cancer stem cells; Head and neck cancer; PDK1; PDK2; TGFβ1.