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The role of LOXL2 induced by glucose metabolism-activated NF-κB in maintaining drug resistance through EMT and cancer stemness in gemcitabine-resistant PDAC

Authors
 Yun Sun Lee  ;  Hyung Sun Kim  ;  Hyo Jung Kim  ;  Hyeon Woong Kang  ;  Da Eun Lee  ;  Myeong Jin Kim  ;  Woosol Chris Hong  ;  Ju Hyun Kim  ;  Minsoo Kim  ;  Jae-Ho Cheong  ;  Joon Seong Park 
Citation
 JOURNAL OF MOLECULAR MEDICINE-JMM, : epub, 2023-10 
Journal Title
JOURNAL OF MOLECULAR MEDICINE-JMM
ISSN
 0946-2716 
Issue Date
2023-10
Keywords
Cancer stem cell ; EMT ; Glucose metabolism ; LOXL2 ; NF-κB ; Pancreatic cancer
Abstract
Gemcitabine is considered a standard treatment for pancreatic cancer, but developing drug resistance greatly limits the effectiveness of chemotherapy and increases the rate of recurrence. Lysyl oxide-like 2 (LOXL2) is highly expressed in pancreatic cancer and is involved in carcinogenesis and EMT regulation. However, studies on the role of LOXL2 in drug resistance are limited. Here, we investigated the mechanism of LOXL2 induction and the effect of LOXL2 on EMT and CSC in gemcitabine-resistant pancreatic cancer. Glucose metabolism was activated in gemcitabine-resistant pancreatic cancer cells, and NF-κB signaling was regulated accordingly. Activated NF-κB directly induces transcription by binding to the promoters of LOXL2 and ZEB1. The EMT process was significantly inhibited by the coregulation of ZEB1 and LOXL2. In addition, LOXL2 inhibition reduced the expression of cancer stemness markers and stemness by regulating MAPK signaling activity. LOXL2 inhibits tumor growth of gemcitabine-resistant pancreatic cancer cells and increases the sensitivity to gemcitabine in mouse models. KEY MESSAGES: We identified a specific mechanism for inducing LOXL2 overexpression in gemcitabine-resistant pancreatic cancer. Taken together, our results suggest LOXL2 has an important regulatory role in maintaining gemcitabine resistance and may be an effective therapeutic target to treat pancreatic cancer.
Full Text
https://link.springer.com/article/10.1007/s00109-023-02369-6
DOI
10.1007/s00109-023-02369-6
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Myeong Jin(김명진) ORCID logo https://orcid.org/0000-0001-7949-5402
Kim, Min Soo(김민수) ORCID logo https://orcid.org/0000-0001-8760-4568
Kim, Hyung Sun(김형선) ORCID logo https://orcid.org/0000-0002-9002-3569
Park, Joon Seong(박준성) ORCID logo https://orcid.org/0000-0001-8048-9990
Cheong, Jae Ho(정재호) ORCID logo https://orcid.org/0000-0002-1703-1781
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/196557
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