Abstract
Neoplastic cells in pancreatic ductual adenocarcinoma (PDAC) survive in an energy-deprived milieu, and hyper-activation of Akt is thought to contribute to the neoplastic cell survival in PDAC. Kras activating mutations, common in PDAC, was believed to be the major driver of Akt activation. However, the inhibitor to Kras was not therapeutic for PDAC patients. This implied that PDAC cells might harbor an intrinsic merit that strengthens Akt activity. Here we showed that BRSK2, a serine/threonine-protein kinase of AMPK family, was induced by nutrient deprivation in PDAC cells and suppressed mTORC1 activity via phosphorylation of tuberous sclerosis complex 2 (TSC2). The suppression of mTORC1 activity in PDAC results in a dominant loss of feedback inhibition on Akt activity by mTORC1, consequently enhancing cell survival. This finding indicates that the intrinsic molecular merit that BRSK2 provides is a survival advantage to PDAC cells and strengthens the invasiveness of these neoplastic cells in energy-deprived environments.
Highlights
pancreatic ductual adenocarcinoma (PDAC), a highly lethal tumor, is rich in desmoplastic stroma and rare in microvasculature, which were considered to be the main barriers to nutrient uptake and drug delivery [1, 2]
We showed that the low-nutrient milieu of PDAC might provide a crucial signaling to Akt activation through upregulation of BRSK2, an AMPK catalytic subunit family member exclusively expressed in pancreas and PDAC cells, enhancing survival of PDAC cells
It has been noted that patients suffering from tuberous sclerosis complex (TSC) do not develop more aggressive tumors like those linked to mutations in PTEN [6], which functions upstream of PI3K/AKT
Summary
PDAC, a highly lethal tumor, is rich in desmoplastic stroma and rare in microvasculature, which were considered to be the main barriers to nutrient uptake and drug delivery [1, 2]. PDAC accumulates the common mutations of epithelial tumors including KRAS, p53, CDKN2 and SMAD [1, 3, 4], PDAC cells are more tolerant to nutrient deprivation and hypoxia than other epithelial-derived tumor cells, and are more resistant to chemotherapy as well [5]. Despite the energy-deprived milieu in PDAC, necrosis is rare in the tumor. These implied that PDAC cells might have some tissue-specific molecules that upregulate the activity of Akt to strengthen the tumor cell survival in nutrientdeprived milieu. These tissue-specific characteristics are not well understood
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
