Novel therapeutic roles of MC-4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinase muscle isozyme M2 and mechanistic target of rapamycin complex 1 pathways

Ji Yeon Son, Sungpil Yoon, In Hwan Tae, Yu Jin Park, Umasankar De, Yukyoung Jeon, Young Ju Park, Im Joo Rhyu, Byung Mu Lee, Kyu Huck Chung, Joung Eun Lim, Se Jeong Lee, Hye Won Lee, Jong Hwan Kwak, Hyung Sik Kim, Han Yong Choi

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Current clinical trials of new anticancer therapies against metastatic renal cell carcinoma (RCC), including molecular-targeted therapies, have not shown promise. The purpose of this study was to preclinically assess the antitumor effects of MC-4, a partially purified material of Artemisia annua L., as a monotherapy or in combination with the known mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, everolimus, against Caki-1 (Von Hippel-Lindau (VHL)+/+) and 786-O (VHL−/−) human RCC cells. MC-4 monotherapy significantly increased tumor growth inhibition and autophagic cell death in RCC cells in vitro and in vivo. Everolimus led to compensatory Akt activation by inhibiting only mTORC1 signaling pathway. In contrast to everolimus, MC-4 enhanced phosphatase and tensin homolog expression and reduced its downstream effector, Akt/pyruvate kinase muscle isozyme M2 (PKM2), leading to decreased expression of glucose transporter 1, which is associated with cancer cell metabolism. The synergistic antitumor and anti-metastatic effects induced by co-administration of MC-4 and everolimus involve cell growth inhibition and autophagic cell death via dual targeting of phosphatidylinositol 3-kinase (PI3K)/Akt/PKM2 and mTORC1. These findings suggest that MC-4 is a novel Akt/PKM2 inhibitor that can overcome the limitation of existing mTOR inhibitors and can be considered a novel strategy to treat patients with rapidly progressing advanced RCC.

Original languageEnglish
Pages (from-to)5083-5095
Number of pages13
JournalCancer medicine
Volume7
Issue number10
DOIs
Publication statusPublished - 2018 Oct

Bibliographical note

Funding Information:
Grant/Award Number: NRF- 2017R1A2B4011780; National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIP), Grant/ Award Number: 2016R1A5A2945889

Funding Information:
We would like to thank the staff of Genia Technologies Inc. for assistance with histopathology in this study. This work was supported by the National Research Foundation of Korea (NRF) Grants funded by the Korean Government (nos. 2016R1A2B2011071;2016R1A4A1011189; 2017R1D1A1B03036571), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (no. NRF-2017R1A2B4011780), and the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIP) (no. 2016R1A5A2945889).

Funding Information:
We would like to thank the staff of Genia Technologies Inc. for assistance with histopathology in this study. This work was supported by the National Research Foundation of Korea (NRF) Grants funded by the Korean Government (nos. 2016R1A2B2011071; 2016R1A4A1011189; 2017R1D1A1B03036571), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (no. NRF-2017R1A2B4011780), and the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIP) (no. 2016R1A5A2945889).

Funding Information:
National Research Foundation of Korea (NRF) Grants funded by the Korean Government, Grant/Award Number: 2016R1A2B2011071 and 2016R1A4A1011189; Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education,

Publisher Copyright:
© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Keywords

  • Artemisia annua L.
  • autophagy
  • everolimus
  • metastatic renal cell carcinoma
  • pyruvate kinase muscle isozyme M2

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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