Hypoxia-induced autophagy of stellate cells inhibits expression and secretion of lumican into microenvironment of pancreatic ductal adenocarcinoma
Authors: Mayrim Rios Perez
Michael Pratt
Michael Kim
Ya&#x27;an Kang
Eugene J Koay
Rolf A Brekken
Xinqun Li
Yeonju Lee
Jason B Fleming
Bingbing Dai
Journal: Cell Death and Differentiation (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Lumican; pancreatic stellate cells; cancer progression; pancreatic adenocarcinoma; hypoxia
Affiliations: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Hamon Center of Therapeutic Oncology Research and Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA., Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ., Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL, USA. .

Abstract:  Lumican is secreted by pancreatic stellate cells and inhibits cancer progression. Extracellular lumican inhibits cancer cell replication and restrains growth of early-stage pancreatic adenocarcinoma (PDAC) such that patients with tumors containing stromal lumican experience a three-fold longer survival after treatment. In the present study, patient tumor tissues, ex-vivo cultures of patient-derived xenografts (PDX), PDAC stellate and tumor cells were used to investigate whether hypoxia (1% O2) within the tumor microenvironment influences stromal lumican expression and secretion. We observed that hypoxia significantly reduced lumican expression and secretion from pancreatic stellate cells, but not cancer cells. Although hypoxia enhanced lactate dehydrogenase A (LDHA) expression and lactate secretion from all cells, neither hypoxia-induced nor exogenous lactate influenced lumican expression. Autophagy was induced by hypoxia in ex vivo cultures of PDX and pancreatic stellate cells, but not cancer cells cultured in 2D. Autophagic flux inhibitors, bafilomycin A1, chloroquine diphosphate salt, and ammonium chloride prevented hypoxia-mediated reduction in lumican expression in stellate cells. Furthermore, inhibition of AMP-regulated protein kinase (AMPK) phosphorylation or hypoxia-inducible factor (HIF)-1α expression within hypoxic stellate cells restored lumican expression levels. Hypoxia did not affect lumican mRNA expression, indicating that hypoxia-induced reduction of lumican occurs post-transcriptionally; in addition, AMPK inhibition prevented hypoxia-reduced phosphorylation of the mTOR/p70S6K/4EBP signaling pathway, a key contributor to protein synthesis. Taken together, these findings demonstrate that hypoxia reduces stromal lumican in PDAC through autophagy-mediated degradation and reduction in protein synthesis within pancreatic cancer stellate cells. 

Retracted: No

PubPeer comments:
 Figures 1A and 4A appear to have an image which overlaps, although the magnification is different. Scale bars are the same. Could the authors please review? *** ![file] , 
 A control band seems to have been used in both Figure 2C and Figure 3F, but to represent different conditions. Could the authors please post the original uncropped scans? Thank you. *** ![file] *** Acknowledgements. This work was supported by grants from the Skip Viragh Family Foundation (to JBF), the W. Smith Foundation (to JBF), National Institutes of Health (NIH) grant T32CA009599 (to MRP), an in-kind grant from the Center for Advanced Biomedical Imaging and GE Healthcare (to EJK and JBF), and U54 CA210181-01 u201cCenter for Immunotherapeutic Transport Oncophysics (CITO)u201d grant (to Koay, Fleming and Brekken). , 
 Figures 1E and 2E seem to share a portion of a HIF-1a band, which has been cropped differently and resized. *** ![file] ,