Induction of ER stress-mediated apoptosis through SOD1 upregulation by deficiency of CHI3L1 inhibits lung metastasis

Sep 24, 2026

Uploaded by Levi

Chitinase-3-like protein 1 (CHI3L1), secreted by immune and inflammatory cells, is linked to inflammatory diseases, yet its core cellular functions remain unclear. Using LC-MS/MS in Myc-CHI3L1-transfected cells, the study identifies 451 differentially expressed proteins enriched for endoplasmic reticulum (ER)–associated functions. CHI3L1 localizes to the ER and depletion triggers ER stress and unfolded protein response via PERK–eIF2α–ATF4, mainly in cancer cells. ER stress-mediated apoptosis increases during tumor growth and lung metastasis in CHI3L1-knockout mice, with SOD1 revealed as a novel CHI3L1 target. Depleting SOD1 reduces ER chaperones and ER-mediated apoptotic markers, supporting SOD1-dependent inhibition of lung metastasis.

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CategoryHealthcare

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Ivyspring International Publisher Theranostics 2023; 13(8): 2693-2709. doi: 10.7150/thno.82898 Research Paper Induction of ER stress-mediated apoptosis through SOD1 upregulation by deficiency of CHI3L1 inhibits lung metastasis Ji Eun Yu*, In Jun Yeo*, Seung Sik Yoo, Sung-hyun Kim, Dong Ju Son, Jaesuk Yun, Sang-Bae Han􀀍, and Jin Tae Hong􀀍 College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Republic of Korea. *: These authors contributed equally to this work. 􀀍 Corresponding authors: Drs. Jin Tae Hong ([jinthong@chungbuk.ac.kr](jinthong@chungbuk.ac.kr)) and Sang-Bae Han ([shan@chungbuk.ac.kr](shan@chungbuk.ac.kr)), College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongiu, Chungbuk, 28160, Republic of Korea, Tel:+82-42-261-2813, Fax: +82-42-268-2732. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [http://ivyspring.com/terms](http://ivyspring.com/terms) for full terms and conditions. Received: 2023.01.24; Accepted: 2023.04.21; Published: 2023.04.29 Abstract Chitinase-3-like protein 1 (CHI3L1), which is secreted by immune and inflammatory cells, is associated with several inflammatory diseases. However, the basic cellular pathophysiological functions of CHI3L1 are not well characterized. To investigate the novel pathophysiological function of CHI3L1, we performed LC-MS/MS analysis of cells transfected with Myc-vector and Myc-CHI3L1. We analyzed the changes in the protein distribution in Myc-CHI3L1 transfected-cells, and identified 451 differentially expressed proteins (DEPs) compared with Myc-vector-transfected-cells. The biological function of the 451 DEPs was analyzed and it was found that the proteins with endoplasmic reticulum (ER)-associated function were much more highly expressed in CHI3L1-overexpressing cells. We then compared and analyzed the effect of CHI3L1 on the ER chaperon levels in normal lung cells and cancer cells. We identified that CHI3L1 is localized in the ER. In normal cells, the depletion of CHI3L1 did not induce ER stress. However, the depletion of CHI3L1 induces ER stress and eventually activates the unfolded protein response, especially the activation of Protein kinase R-like endoplasmic reticulum kinase (PERK), which regulates protein synthesis in cancer cells. CHI3L1 may not affect ER stress owing to the lack of misfolded proteins in normal cells, but instead activate ER stress as a defense mechanism only in cancer cells. Under ER stress conditions induced by the application of thapsigargin, the depletion of CHI3L1 induces ER stress through the upregulation of PERK and PERK downstream factors (eIF2α and ATF4) in both normal and cancer cells. However, these signaling activations occur more often in cancer cells than in normal cells. The expression of Grp78 and PERK in the tissues of patients with lung cancer was higher compared with healthy tissues. It is well known that ER stress-mediated PERK–eIF2α–ATF4 signaling activation causes apoptotic cell death. ER stress-mediated apoptosis induced by the depletion of CHI3L1 occurs in cancer cells, but rarely occurs in normal cells. Consistent with results from the in vitro model, ER stress-mediated apoptosis was greatly increased during tumor growth and in the lung metastatic tissue of CHI3L1-knockout (KO) mice. The analysis of “big data” identified superoxide dismutase-1 (SOD1) as a novel target of CHI3L1 and interacted with CHI3L1. The depletion of CHI3L1 increased SOD1 expression, resulting in ER stress. Furthermore, the depletion of SOD1 reduced the expression of ER chaperones and ER-mediated apoptotic marker proteins, as well as apoptotic cell death induced by the depletion of CHI3L1 in i

FAQs

What is CHI3L1 and what cellular role is investigated in this paper?

CHI3L1 is a secreted chitinase-3-like protein associated with inflammatory diseases. The paper investigates its cellular pathophysiological functions, focusing on ER-related mechanisms and apoptosis.

How does CHI3L1 depletion affect ER stress and the unfolded protein response?

In cancer cells, CHI3L1 depletion induces ER stress and activates the unfolded protein response, especially PERK, followed by downstream signaling involving eIF2α and ATF4. In normal cells, depletion does not induce ER stress under baseline conditions.

What role does SOD1 play in CHI3L1-dependent ER stress and lung metastasis?

Big-data analysis identifies SOD1 as a novel CHI3L1 target that interacts with CHI3L1. CHI3L1 depletion increases SOD1 expression and drives ER stress and apoptosis; SOD1 depletion reduces ER chaperones, apoptotic markers, and apoptosis triggered by CHI3L1 loss, supporting inhibition of lung metastasis.

Sep 24, 2026

Uploaded by Levi