Biomol Ther  
Transglutaminase 2 Promotes Autophagy by LC3 Induction Through p53 Depletion in Cancer Cell
Joon Hee Kang1,2, Seon-Hyeong Lee1, Heesun Cheong1, Chang Hoon Lee2,* and Soo-Youl Kim1,*
1Tumor Microenvironment Research Branch, Division of Cancer Biology, Research Institute, Goyang 10408,
2College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea
E-mail: kimsooyoul@gmail.com (Kim SY), uatheone@dongguk.edu (Lee CH)
Tel: +82-31-920-2221 (Kim SY), +82-31-961-5213 (Lee CH)
Fax: +82-31-920-2006 (Kim SY), +82-31-961-5206 (Lee CH)
Received: July 23, 2018; Revised: July 31, 2018; Accepted: August 8, 2018; Published online: September 20, 2018.
© The Korean Society of Applied Pharmacology. All rights reserved.

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.
Keywords: Transglutaminase 2, Autophagy, LC3, p53, Cancer cell


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