Novel role of miR-29a in pancreatic cancer autophagy and its therapeutic potential.
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal malignancy that responds poorly to current therapeutic modalities. In an effort to develop novel therapeutic strategies, we found downregulation of miR-29 in pancreatic cancer cells, and overexpression of miR-29a sensitized chemotherapeutic resistant pancreatic cancer cells to gemcitabine, reduced cancer cell viability, and increased cytotoxicity. Furthermore, miR-29a blocked autophagy flux, as evidenced by an accumulation of autophagosomes and autophagy markers, LC3B and p62, and a decrease in autophagosome-lysosome fusion. In addition, miR-29a decreased the expression of autophagy proteins, TFEB and ATG9A, which are critical for lysosomal function and autophagosome trafficking respectively. Knockdown of TFEB or ATG9A inhibited autophagy similar to miR-29a overexpression. Finally, miR-29a reduced cancer cell migration, invasion, and anchorage independent growth. Collectively, our findings indicate that miR-29a functions as a potent autophagy inhibitor, sensitizes cancer cells to gemcitabine, and decreases their invasive potential. Our data provides evidence for the use of miR-29a as a novel therapeutic agent to target PDAC.
Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.
Jason J
JJ
Kwon
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.
Jeffrey A
JA
Willy
Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.
Kayla A
KA
Quirin
Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.
Ronald C
RC
Wek
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.|Department of Medicine, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.|The Melvin and Bren Simon Cancer Center, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.|Center for Pancreatic Cancer Research, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN, USA.
Murray
M
Korc
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.
Xiao-Ming
XM
Yin
Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.|The Melvin and Bren Simon Cancer Center, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.|Center for Pancreatic Cancer Research, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN, USA.
Janaiah
J
Kota
D001343:Autophagy; D000071183:Autophagy-Related Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D035683:MicroRNAs / Q000502:physiology*; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D033921:Vesicular Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D000093542:Gemcitabine
C574794:ATG9A protein, human; D000071183:Autophagy-Related Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C532045:MIRN29a microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C064972:TFEB protein, human; D033921:Vesicular Transport Proteins; D003841:Deoxycytidine; D000093542:Gemcitabine
autophagy; gemcitabine; metastasis; miR-29; pancreatic cancer