Interleukin-1 alpha and high mobility group box-1 secretion in polyinosinic:polycytidylic-induced colorectal cancer cells occur via RIPK1-dependent mechanism and participate in tumourigenesis

Pathogenic infections have significant roles in the pathogenesis of colorectal cancer (CRC). These infections induce the secretion of various damage-associated molecular patterns (DAMPs) including interleukin-1 alpha (IL-1 alpha) and high mobility group box-1 (HMGB1). Despite their implication in CR...

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Main Authors: Cheng, Kim Jun, Mohamed, Elsa Haniffah Mejia, Syafruddin, Saiful Effendi, Ibrahim, Zaridatul Aini
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Published: Springer 2023
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Online Access:http://eprints.um.edu.my/39554/
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spelling my.um.eprints.395542024-11-24T12:34:06Z http://eprints.um.edu.my/39554/ Interleukin-1 alpha and high mobility group box-1 secretion in polyinosinic:polycytidylic-induced colorectal cancer cells occur via RIPK1-dependent mechanism and participate in tumourigenesis Cheng, Kim Jun Mohamed, Elsa Haniffah Mejia Syafruddin, Saiful Effendi Ibrahim, Zaridatul Aini RC Internal medicine RC0254 Neoplasms. Tumors. Oncology (including Cancer) Pathogenic infections have significant roles in the pathogenesis of colorectal cancer (CRC). These infections induce the secretion of various damage-associated molecular patterns (DAMPs) including interleukin-1 alpha (IL-1 alpha) and high mobility group box-1 (HMGB1). Despite their implication in CRC pathogenesis, the mechanism(s) that modulate the secretion of IL-1 alpha and HMGB1, along with their roles in promoting CRC tumourigenesis remain poorly understood. To understand the secretory mechanism, HT-29 and SW480 cells were stimulated with infectious mimetics; polyinosinic:polycytidylic acid Poly(I:C)], lipopolysaccharide (LPS) and pro-inflammatory stimuli; tumour necrosis factor-alpha (TNF-alpha). IL-1 alpha and HMGB1 secretion levels upon stimulation were determined via ELISA. Mechanism(s) mediating IL-1 alpha and HMGB1 secretion in CRC cells were characterized using pharmacological inhibitors and CRISPR-Cas9 gene editing targeting relevant pathways. Recombinant IL-1 alpha and HMGB1 were utilized to determine their impact in modulating pro-tumourigenic properties of CRC cells. Pharmacological inhibition showed that Poly(I:C)-induced IL-1 alpha secretion was mediated through endoplasmic reticulum (ER) stress and RIPK1 signalling pathway. The secretion of HMGB1 was RIPK1-dependent but independent of ER stress. RIPK1-targeted CRC cell pools exhibited decreased cell viability upon Poly(I:C) stimulation, suggesting a potential role of RIPK1 in CRC cells survival. IL-1 alpha has both growth-promoting capabilities and stimulates the production of pro-metastatic mediators, while HMGB1 only exhibits the latter; with its redox status having influence. We demonstrated a potential role of RIPK1-dependent signalling pathway in mediating the secretion of IL-1 alpha and HMGB1 in CRC cells, which in turn enhances CRC tumorigenesis. RIPK1, IL-1 alpha and HMGB1 may serve as potential therapeutic targets to mitigate CRC progression. Springer 2023-03 Article PeerReviewed Cheng, Kim Jun and Mohamed, Elsa Haniffah Mejia and Syafruddin, Saiful Effendi and Ibrahim, Zaridatul Aini (2023) Interleukin-1 alpha and high mobility group box-1 secretion in polyinosinic:polycytidylic-induced colorectal cancer cells occur via RIPK1-dependent mechanism and participate in tumourigenesis. Journal of Cell Communication and Signaling, 17 (1). pp. 189-208. ISSN 18739601, DOI https://doi.org/10.1007/s12079-022-00681-3 <https://doi.org/10.1007/s12079-022-00681-3>. 10.1007/s12079-022-00681-3
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
topic RC Internal medicine
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
spellingShingle RC Internal medicine
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Cheng, Kim Jun
Mohamed, Elsa Haniffah Mejia
Syafruddin, Saiful Effendi
Ibrahim, Zaridatul Aini
Interleukin-1 alpha and high mobility group box-1 secretion in polyinosinic:polycytidylic-induced colorectal cancer cells occur via RIPK1-dependent mechanism and participate in tumourigenesis
description Pathogenic infections have significant roles in the pathogenesis of colorectal cancer (CRC). These infections induce the secretion of various damage-associated molecular patterns (DAMPs) including interleukin-1 alpha (IL-1 alpha) and high mobility group box-1 (HMGB1). Despite their implication in CRC pathogenesis, the mechanism(s) that modulate the secretion of IL-1 alpha and HMGB1, along with their roles in promoting CRC tumourigenesis remain poorly understood. To understand the secretory mechanism, HT-29 and SW480 cells were stimulated with infectious mimetics; polyinosinic:polycytidylic acid Poly(I:C)], lipopolysaccharide (LPS) and pro-inflammatory stimuli; tumour necrosis factor-alpha (TNF-alpha). IL-1 alpha and HMGB1 secretion levels upon stimulation were determined via ELISA. Mechanism(s) mediating IL-1 alpha and HMGB1 secretion in CRC cells were characterized using pharmacological inhibitors and CRISPR-Cas9 gene editing targeting relevant pathways. Recombinant IL-1 alpha and HMGB1 were utilized to determine their impact in modulating pro-tumourigenic properties of CRC cells. Pharmacological inhibition showed that Poly(I:C)-induced IL-1 alpha secretion was mediated through endoplasmic reticulum (ER) stress and RIPK1 signalling pathway. The secretion of HMGB1 was RIPK1-dependent but independent of ER stress. RIPK1-targeted CRC cell pools exhibited decreased cell viability upon Poly(I:C) stimulation, suggesting a potential role of RIPK1 in CRC cells survival. IL-1 alpha has both growth-promoting capabilities and stimulates the production of pro-metastatic mediators, while HMGB1 only exhibits the latter; with its redox status having influence. We demonstrated a potential role of RIPK1-dependent signalling pathway in mediating the secretion of IL-1 alpha and HMGB1 in CRC cells, which in turn enhances CRC tumorigenesis. RIPK1, IL-1 alpha and HMGB1 may serve as potential therapeutic targets to mitigate CRC progression.
format Article
author Cheng, Kim Jun
Mohamed, Elsa Haniffah Mejia
Syafruddin, Saiful Effendi
Ibrahim, Zaridatul Aini
author_facet Cheng, Kim Jun
Mohamed, Elsa Haniffah Mejia
Syafruddin, Saiful Effendi
Ibrahim, Zaridatul Aini
author_sort Cheng, Kim Jun
title Interleukin-1 alpha and high mobility group box-1 secretion in polyinosinic:polycytidylic-induced colorectal cancer cells occur via RIPK1-dependent mechanism and participate in tumourigenesis
title_short Interleukin-1 alpha and high mobility group box-1 secretion in polyinosinic:polycytidylic-induced colorectal cancer cells occur via RIPK1-dependent mechanism and participate in tumourigenesis
title_full Interleukin-1 alpha and high mobility group box-1 secretion in polyinosinic:polycytidylic-induced colorectal cancer cells occur via RIPK1-dependent mechanism and participate in tumourigenesis
title_fullStr Interleukin-1 alpha and high mobility group box-1 secretion in polyinosinic:polycytidylic-induced colorectal cancer cells occur via RIPK1-dependent mechanism and participate in tumourigenesis
title_full_unstemmed Interleukin-1 alpha and high mobility group box-1 secretion in polyinosinic:polycytidylic-induced colorectal cancer cells occur via RIPK1-dependent mechanism and participate in tumourigenesis
title_sort interleukin-1 alpha and high mobility group box-1 secretion in polyinosinic:polycytidylic-induced colorectal cancer cells occur via ripk1-dependent mechanism and participate in tumourigenesis
publisher Springer
publishDate 2023
url http://eprints.um.edu.my/39554/
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