Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Transglutaminase 2 Promotes Autophagy by LC3 Induction through p53 Depletion in Cancer Cell

  • Kang, Joon Hee (Tumor Microenvironment Research Branch, Division of Cancer Biology, Research Institute, National Cancer Center) ;
  • Lee, Seon-Hyeong (Tumor Microenvironment Research Branch, Division of Cancer Biology, Research Institute, National Cancer Center) ;
  • Cheong, Heesun (Tumor Microenvironment Research Branch, Division of Cancer Biology, Research Institute, National Cancer Center) ;
  • Lee, Chang Hoon (College of Pharmacy, Dongguk University) ;
  • Kim, Soo-Youl (Tumor Microenvironment Research Branch, Division of Cancer Biology, Research Institute, National Cancer Center)
  • Received : 2018.07.23
  • Accepted : 2018.08.08
  • Published : 2019.01.01
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Abstract

Transglutaminase 2 (TGase 2) plays a key role in p53 regulation, depleting p53 tumor suppressor through autophagy in renal cell carcinoma. We found that microtubule-associated protein 1A/1B-light chain 3 (LC3), a hallmark of autophagy, were tightly associated with the level of TGase 2 in cancer cells. TGase 2 overexpression increased LC3 levels, and TGase 2 knockdown decreased LC3 levels in cancer cells. Transcript abundance of LC3 was inversely correlated with level of wild type p53. TGase 2 knockdown using siRNA, or TGase 2 inhibition using GK921 significantly reduced autophagy through reduction of LC3 transcription, which was followed by restoration of p53 levels in cancer cells. TGase 2 overexpression promoted the autophagy process by LC3 induction, which was correlated with p53 depletion in cancer cells. Rapamycin-resistant cancer cells also showed higher expression of LC3 compared to the rapamycin-sensitive cancer cells, which was tightly correlated with TGase 2 levels. TGase 2 knockdown or TGase 2 inhibition sensitized rapamycin-resistant cancer cells to drug treatment. In summary, TGase 2 induces drug resistance by potentiating autophagy through LC3 induction via p53 regulation in cancer.

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References

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