The HIF-1–Inducible Lysyl Oxidase Activates HIF-1 via the Akt Pathway in a Positive Regulation Loop and Synergizes with HIF-1 in Promoting Tumor Cell Growth
Floriane Pez,Frédéric Dayan,Jérôme Durivault,Bastien Kaniewski,Géraldine Aimond,Gabrielle S. Le Provost,Blandine Deux,Philippe Clézardin,Pascal Sommer,Jacques Pouysségur,Caroline Reynaud +10 more
TLDR
Mechanistic investigations revealed that LOX activated the PI3K (phosphoinositide 3-kinase)-Akt signaling pathway, thereby upregulating HIF-1α protein synthesis in a manner requiring LOX-mediated hydrogen peroxide production, suggesting that Hif-1/LOX mutual regulation is a pivotal mechanism in the adaptation of tumor cells to hypoxia.Abstract:
Adaptation to hypoxia is a driving force for tumor progression that leads to therapy resistance and poor clinical outcome. Hypoxic responses are mainly mediated by hypoxia-inducible transcription factor-1 (HIF-1). One critical HIF-1 target mediating tumor progression is lysyl oxidase (LOX), which catalyzes cross-linking of collagens and elastin in the extracellular matrix, thereby regulating tissue tensile strength. Paradoxically, LOX has been reported to be both upregulated and downregulated in cancer cells, especially in colorectal cancer. Thus, we hypothesized that LOX might regulate expression of HIF-1 to create a self-timing regulatory circuit. Using human colorectal carcinoma cell lines in which HIF-1 and LOX expression could be modulated, we showed that LOX induction enhanced HIF-1 expression, whereas LOX silencing reduced it. Mechanistic investigations revealed that LOX activated the PI3K (phosphoinositide 3-kinase)-Akt signaling pathway, thereby upregulating HIF-1α protein synthesis in a manner requiring LOX-mediated hydrogen peroxide production. Consistent with these results, cancer cell proliferation was stimulated by secreted and active LOX in an HIF-1α-dependent fashion. Furthermore, nude mice xenograft assays established that HIF-1 potentiated LOX action on tumor growth in vivo. Taken together, these findings provide compelling evidence that LOX and HIF-1 act in synergy to foster tumor formation, and they suggest that HIF-1/LOX mutual regulation is a pivotal mechanism in the adaptation of tumor cells to hypoxia.read more
Citations
More filters
Journal ArticleDOI
The rationale for targeting the LOX family in cancer.
TL;DR: The roles of members of the lysyl oxidase (LOX) family in the remodelling of the tumour microenvironment and their paradoxical roles in tumorigenesis and metastasis are discussed.
Journal ArticleDOI
Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK.
Ann-Marie Baker,Demelza Bird,Georgina Lang,Thomas R. Cox,Thomas R. Cox,Janine T. Erler,Janine T. Erler +6 more
TL;DR: It is shown that catalytic activity is required for LOX-mediated effects on proliferation and invasion in both in vitro and in vivo models of CRC, and a role for stiffness in driving CRC progression is demonstrated.
Journal ArticleDOI
Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy
Christelle P. El-Haibi,George W. Bell,Jiangwen Zhang,Anthony Y. Collmann,David K. Wood,Cally M. Scherber,Eva Csizmadia,Odette Mariani,Cuihua Zhu,Antoine Campagne,Antoine Campagne,Mehmet Toner,Sangeeta N. Bhatia,Daniel Irimia,Anne Vincent-Salomon,Antoine E. Karnoub +15 more
TL;DR: It is shown that bone marrow-derived human MSCs promote de novo production of lysyl oxidase (LOX) from human breast carcinoma cells, which is sufficient to enhance the metastasis of otherwise weakly metastatic cancer cells to the lungs and bones and indicates that the signaling pathways controlling stroma-induced EMT are distinct from pathways regulating the development of cancer stem cells.
Journal ArticleDOI
Lysyl Oxidase, Extracellular Matrix Remodeling and Cancer Metastasis
Qian Xiao,Gaoxiang Ge +1 more
TL;DR: This review will summarize the recent progress on LOX family oxidases, with much of the focus on the roles and mechanism of LOX in tumor progression and metastasis.
Journal ArticleDOI
Symbiotic Macrophage-Glioma Cell Interactions Reveal Synthetic Lethality in PTEN-Null Glioma
Peiwen Chen,Di Zhao,Jun Li,Xin Liang,Jiexi Li,Andrew Chang,Verlene Henry,Zhengdao Lan,Denise J. Spring,Ganesh Rao,Y. Alan Wang,Ronald A. DePinho +11 more
TL;DR: It is established that PTEN deficiency activates YAP1, which directly upregulates lysyl oxidase (LOX) expression, which facilitates symbiotic glioma-macrophage interplay and provides therapeutic targets specifically for PTEN-deficient GBM patients.
References
More filters
Journal ArticleDOI
Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling
Kandice R. Levental,Hongmei Yu,Laura Kass,Johnathon N. Lakins,Mikala Egeblad,Janine T. Erler,Sheri F. T. Fong,Katalin Csiszar,Amato J. Giaccia,Wolfgang Weninger,Mitsuo Yamauchi,David L. Gasser,Valerie M. Weaver +12 more
TL;DR: Reduction of lysyl oxidase-mediated collagen crosslinking prevented MMTV-Neu-induced fibrosis, decreased focal adhesions and PI3K activity, impeded malignancy, and lowered tumor incidence, and data show how collagenCrosslinking can modulate tissue fibrosis and stiffness to force focal adhesion, growth factor signaling and breast malignancies.
Journal ArticleDOI
Hypoxia signalling in cancer and approaches to enforce tumour regression
TL;DR: There are new approaches to enforce necrotic cell death and tumour regression by targeting tumour metabolism and pHi-control systems.
Journal ArticleDOI
Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics
TL;DR: This review summarizes the current state of knowledge regarding the molecular mechanisms by which Hif-1 contributes to cancer progression, focusing on clinical data associating increased HIF-1 levels with patient mortality and pharmacological data showing anticancer effects of H IF-1 inhibitors in mouse models of human cancer.
Journal Article
Modulation of Hypoxia-inducible Factor 1α Expression by the Epidermal Growth Factor/Phosphatidylinositol 3-Kinase/PTEN/AKT/FRAP Pathway in Human Prostate Cancer Cells: Implications for Tumor Angiogenesis and Therapeutics
Hua Zhong,Kelly Chiles,David M. Feldser,Erik Laughner,Colleen Hanrahan,Maria Magdalena Georgescu,Jonathan W. Simons,Gregg L. Semenza +7 more
TL;DR: It is demonstrated that in human prostate cancer cells, basal-, growth factor- and mitogen-induced expression of hypoxia-inducible factor 1 (HIF-1) alpha, the regulated subunit of the transcription factor Hif-1, is blocked by LY294002 and rapamycin, inhibitors of PI3K and FRAP, respectively.
Journal ArticleDOI
Lysyl oxidase is essential for hypoxia-induced metastasis
Janine T. Erler,Kevin L. Bennewith,Monica Nicolau,Nadja Dornhöfer,Christina S. Kong,Quynh-Thu Le,Jen-Tsan Ashley Chi,Stefanie S. Jeffrey,Amato J. Giaccia +8 more
TL;DR: It is shown that LOX expression is regulated by hypoxia-inducible factor (HIF) and is associated with Hypoxia in human breast and head and neck tumours, and is a good therapeutic target for preventing and treating metastases.
Related Papers (5)
Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment.
Vivian Barry-Hamilton,Rhyannon Spangler,Derek Marshall,Scott Alan Mccauley,Hector Rodriguez,Miho Oyasu,Amanda Mikels,Maria Vaysberg,Haben Ghermazien,Carol Wai,Carlos Aurelio Garcia,Arleene C. Velayo,Brett Jorgensen,Donna Hiroko Tokuoka Biermann,Daniel Tsai,Jennifer Green,Shelly Zaffryar-Eilot,Alison Kay Holzer,Scott Ogg,Dung Thai,Gera Neufeld,Peter Van Vlasselaer,Victoria Smith +22 more