A positive feedback between HIF1α and lysyl oxidase-like 2 dictates the Warburg Effect in Pancreatic Cancer

Abstract Background Hypoxic microenvironment is common in solid tumors, particularly in pancreatic ductal adenocarcinoma (PDAC). The Warburg effect is known to facilitate cancer aggressiveness and has long been linked to hypoxia, yet the underlying mechanism remains largely unknown. Methods The expression pattern and prognostic value of LOXL2 was analyzed by immunohistochemistry. The effects of LOXL2 on cancer cell proliferation, migration, and invasion in vitro, tumor growth and metastasis in vivo were investigated by genetic manipulation of LOXL2 expression in human PDAC cell lines. The effects of LOXL2 on aerobic glycolysis were examined by glucose uptake, lactate production, and Seahorse Flux Analyzer. Quantitative real-time PCR, western blotting, immunofluorescence and other techniques were conducted to identify molecular mechanism. Results Lysyl oxidase-like 2 (LOXL2) is a hypoxia-responsive gene and is essential for the Warburg effect in pancreatic ductal adenocarcinoma (PDAC). LOXL2 stabilizes hypoxia-inducible factor 1α (HIF1α) from prolyl hydroxylase (PHD)-dependent hydroxylation via hydrogen peroxide generation, thereby facilitating the transcription of multiple glycolytic genes. Therefore, a positive feedback loop is existed between LOXL2 and HIF1α that facilitates glycolytic metabolism under hypoxia. LOXL2 couples the Warburg effect to tumor growth and metastasis in PDAC. Hijacking glycolysis largely compromises LOXL2-induced oncogenic activities. Conclusion Our results identify a hitherto unknown hypoxia-LOXL2-HIF1α axis in regulating the Warburg effect and provide an intriguing drug target for PDAC therapy.

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Reciprocal regulation of LOXL2 and HIF1α drives the Warburg effect to support pancreatic cancer aggressiveness

Cell Death and Disease ◽

10.1038/s41419-021-04391-3 ◽

2021 ◽

Vol 12 (12) ◽

Author(s):

Rongkun Li ◽

Hengchao Li ◽

Lili Zhu ◽

Xiaoxin Zhang ◽

Dejun Liu ◽

...

Keyword(s):

Warburg Effect ◽

Lysyl Oxidase ◽

Hypoxia Inducible Factor ◽

Underlying Mechanism ◽

Ductal Adenocarcinoma ◽

Reciprocal Regulation ◽

Cancer Aggressiveness ◽

Tumor Growth And Metastasis ◽

Hydrogen Peroxide Generation ◽

The Warburg Effect

AbstractHypoxic microenvironment is common in solid tumors, particularly in pancreatic ductal adenocarcinoma (PDAC). The Warburg effect is known to facilitate cancer aggressiveness and has long been linked to hypoxia, yet the underlying mechanism remains largely unknown. In this study, we identify that lysyl oxidase-like 2 (LOXL2) is a hypoxia-responsive gene and is essential for the Warburg effect in PDAC. LOXL2 stabilizes hypoxia-inducible factor 1α (HIF1α) from prolyl hydroxylase (PHD)-dependent hydroxylation via hydrogen peroxide generation, thereby facilitating the transcription of multiple glycolytic genes. Therefore, a positive feedback loop exists between LOXL2 and HIF1α that facilitates glycolytic metabolism under hypoxia. Moreover, LOXL2 couples the Warburg effect to tumor growth and metastasis in PDAC. Hijacking glycolysis largely compromises LOXL2-induced oncogenic activities. Collectively, our results identify a hitherto unknown hypoxia-LOXL2-HIF1α axis in regulating the Warburg effect and provide an intriguing drug target for PDAC therapy.

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Tumor-associated macrophages promote progression and the Warburg effect via CCL18/NF-kB/VCAM-1 pathway in pancreatic ductal adenocarcinoma

Cell Death and Disease ◽

10.1038/s41419-018-0486-0 ◽

2018 ◽

Vol 9 (5) ◽

Cited By ~ 39

Author(s):

Huilin Ye ◽

Quanbo Zhou ◽

Shangyou Zheng ◽

Guolin Li ◽

Qing Lin ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Warburg Effect ◽

Ductal Adenocarcinoma ◽

Tumor Associated Macrophages ◽

The Warburg Effect

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Increased semaphorin 3c expression promotes tumor growth and metastasis in pancreatic ductal adenocarcinoma by activating the ERK1/2 signaling pathway

Cancer Letters ◽

10.1016/j.canlet.2017.03.014 ◽

2017 ◽

Vol 397 ◽

pp. 12-22 ◽

Cited By ~ 16

Author(s):

Xuejun Xu ◽

Zhiping Zhao ◽

Shixiang Guo ◽

Jian Li ◽

Songsong Liu ◽

...

Keyword(s):

Tumor Growth ◽

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathway ◽

Ductal Adenocarcinoma ◽

Tumor Growth And Metastasis

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Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells

Nature Communications ◽

10.1038/s41467-021-22490-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Chenxi Tian ◽

Ying Huang ◽

Karl R. Clauser ◽

Steffen Rickelt ◽

Allison N. Lau ◽

...

Keyword(s):

Tumor Growth ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Cells ◽

Cancer Cell ◽

Stromal Cells ◽

Proteinase Activity ◽

Ductal Adenocarcinoma ◽

Fibrillar Collagen ◽

Fibrillar Collagens ◽

Tumor Growth And Metastasis

AbstractPancreatic ductal adenocarcinoma (PDAC) has a collagen-rich dense extracellular matrix (ECM) that promotes malignancy of cancer cells and presents a barrier for drug delivery. Data analysis of our published mass spectrometry (MS)-based studies on enriched ECM from samples of progressive PDAC stages reveal that the C-terminal prodomains of fibrillar collagens are partially uncleaved in PDAC ECM, suggesting reduced procollagen C-proteinase activity. We further show that the enzyme responsible for procollagen C-proteinase activity, bone morphogenetic protein1 (BMP1), selectively suppresses tumor growth and metastasis in cells expressing high levels of COL1A1. Although BMP1, as a secreted proteinase, promotes fibrillar collagen deposition from both cancer cells and stromal cells, only cancer-cell-derived procollagen cleavage and deposition suppresses tumor malignancy. These studies reveal a role for cancer-cell-derived fibrillar collagen in selectively restraining tumor growth and suggest stratification of patients based on their tumor epithelial collagen I expression when considering treatments related to perturbation of fibrillar collagens.

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