Premium
Therapeutic effect of MC‐4 in combination with everolimus against progressive renal cell carcinoma by double‐targeting of PTEN/AKT/PKM2 and mTOR1 signaling pathways
Author(s) -
Jiyeong Kim
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.lb678
Subject(s) - everolimus , pi3k/akt/mtor pathway , protein kinase b , pkm2 , cancer research , mtorc1 , pten , autophagy , cell growth , pharmacology , chemistry , apoptosis , medicine , biology , oncology , pyruvate kinase , biochemistry , glycolysis , enzyme
The purpose of this study was to assess the antitumor effects of MC‐4, a novel compound extracted from Artemisia annua L., as a monotherapy or combined with everolimus against Caki‐1 (Von Hippel‐Lindau (VHL)+/+) and 786‐O (VHL−/−) human RCC cells in vitro and in vivo . RCC cells were treated with MC‐4 alone or combined with everolimus and were analyzed for viability, apoptosis, and autophagy to evaluate synergistic antitumor effects in vitro and in xenograft in vivo models. MC‐4 inhibited Akt and pyruvate kinase M2 (PKM2), and significantly increased growth inhibition and autophagic cell death in RCC cells. However, everolimus led to compensatory Akt activation by inhibiting only the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. In contrast to everolimus, MC‐4 enhanced phosphatase and tensin homolog (PTEN) expression and reduced its downstream effector, PKM2, leading to decreased expression of glucose transporter 1 (GLUT1) associated with cancer cell metabolism. Collectively, the synergistic cytotoxic effects induced by co‐administration of MC‐4 and everolimus involve cell growth inhibition and autophagic cell death via dual targeting of Akt/PKM2 and mTOR. This suggests that MC‐4 is a novel Akt/PKM2 inhibitor that could overcome the limitation of existing mTOR inhibitors used for mRCC therapy. The data herein encourage further clinical studies combining MC‐4 with established chemotherapeutics as a strategy to treat patients with rapidly progressing RCC. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .