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 journalArticle

3 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
JournalCancer Medicine
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

Renal Cell Carcinoma
Autophagy
Artemisia annua
Phosphatidylinositol 3-Kinase
Molecular Targeted Therapy
Facilitative Glucose Transport Proteins
Therapeutics
Growth
Phosphoric Monoester Hydrolases
Neoplasms
Clinical Trials
mechanistic target of rapamycin complex 1
thyroid hormone-binding proteins
Everolimus

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

Cite this

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

In: Cancer Medicine, 01.01.2018.

Research output: Contribution to journalArticle

Son, Ji Yeon ; Yoon, Sungpil ; Tae, In Hwan ; Park, Yu Jin ; De, Umasankar ; Jeon, Yukyoung ; Park, Young Ju ; Rhyu, Im Joo ; Lee, Byung Mu ; Chung, Kyu Huck ; Lim, Joung Eun ; Lee, Se Jeong ; Lee, Hye Won ; Kwak, Jong Hwan ; Kim, Hyung Sik ; Choi, Han Yong. / 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. In: Cancer Medicine. 2018.
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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.",
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AU - Tae, In Hwan

AU - Park, Yu Jin

AU - De, Umasankar

AU - Jeon, Yukyoung

AU - Park, Young Ju

AU - Rhyu, Im Joo

AU - Lee, Byung Mu

AU - Chung, Kyu Huck

AU - Lim, Joung Eun

AU - Lee, Se Jeong

AU - Lee, Hye Won

AU - Kwak, Jong Hwan

AU - Kim, Hyung Sik

AU - Choi, Han Yong

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