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Knockdown and Inhibition of SYK Tyrosine Kinase Decreases mTORC1 Activity and Enhances Lysosomal Biogenesis and Autolysosomal Maturation in Pancreatic Cancer Cell Lines
Author(s) -
Pan Michelle,
Hua Kevin,
Villait Akash,
Zuger Angelina,
Rafati Minoo,
Chen Ryan,
Liu Sherry,
Singh Anurag
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.01879
Subject(s) - tfeb , syk , mtorc1 , microbiology and biotechnology , kras , autophagy , cancer research , biology , transcription factor , pi3k/akt/mtor pathway , pancreatic cancer , chemistry , tyrosine kinase , signal transduction , cancer , apoptosis , biochemistry , colorectal cancer , genetics , gene
In cancer, oncogene dependency is a phenomenon where a dominant driver oncogene promotes tumor cell proliferation and survival, and loss of this oncogene results in tumor cell death and, eventually, tumor regression. KRAS, a GTPase that regulates cell growth and proliferation, is an oncogene constitutively activated in over 90% of pancreatic cancer. However, clinically effective inhibitors of KRAS have been unsuccessful so efforts have been focused on identifying other potential targets associated with the KRAS signaling network. Spleen tyrosine kinase (SYK), expressed at high levels in KRAS‐dependent pancreatic cancer cell lines, may be one of these targets. Our data indicate that SYK activates the mechanistic target of rapamycin kinase complex 1 (mTORC1), which promotes protein translation and cell growth. SYK activation also leads to decreased autolysosome count. In connecting SYK activation with increase mTORC1 activity and decrease autolysosome count, we hypothesis that the MiT/TFE transcription factors are involved. We propose that SYK inhibition in pancreatic cancer cells leads to reduced mTORC1 activity, which reduces phosphorylation of MiT/TFE transcription factors. The unphosphorylated MiT/TFE transcription factors are then allowed into the nucleus to activate genes for lysosomal biogenesis and autophagy. Autophagy is a process that recycles cellular macromolecules during nutrient deprivation by fusing autophagosomes and lysosomes, produced from lysosomal biogenesis, to generate autolysosomes. From our experiments, we were able to show that SYK inhibition blocks mTORC1‐dependent phosphorylation of MITF and TFEB transcription factors, members of the MiT/TFE family. MITF and TFEB activation leads to increased autophagy due to autolysosomal biogenesis and accumulation. In summary, our studies of the SYK‐mTORC1‐autophagy pathway provide support to investigate SYK as a candidate, therapeutic target for pancreatic cancer treatment. Support or Funding Information NIH/NCI K99/R00 ‐ Anurag Singh (PI); Boston University Dahod Breast Cancer Pilot Award ‐ Anurag Singh (PI); Boston University's Undergraduate Research Opportunities Program ‐ Michelle Pan