Abstract
Pancreatic cancer is amongst the most lethal malignancies, while its
poor prognosis could be associated with promotion of autophagy and the
tumor immune microenvironment. Studies have confirmed the
pro-tumorigenic nature of the cathelicidin family of peptide LL-37 in
several types of cancer. However, at higher doses, LL-37 exerts
significant cytotoxicity against gastrointestinal cancer cells. In our
study, we investigated the anti-tumorigenic potential of LL-37 in
pancreatic cancer and the underlying mechanisms. Our results have shown
that LL-37 inhibited the growth of pancreatic cancer both in vitro and in vivo.
Mechanistic studies have demonstrated that LL-37 induced DNA damage and
cell cycle arrest through induction of reactive oxygen species (ROS).
Further study indicates that LL-37 suppressed autophagy in pancreatic
cancer cells through activation of mTOR signaling, leading to more
accumulation of ROS production and induction of mitochondrial
dysfunctions. With combined treatment of LL-37 with the mTOR inhibitor
rapamycin, LL-37-induced ROS production and cancer cell growth
inhibition were attenuated. Subsequent in vivo study has shown
that LL-37 downregulated the immunosuppressive myeloid-derived
suppressor cells and M2 macrophages while upregulated the anti-cancer
effectors CD8+ and CD4+ T cells in the tumor microenvironment. By using an in vitro
co-culture system, it was shown that promotion of M2 macrophage
polarization would be suppressed by LL-37 with inhibition of autophagy,
which possessed significant negative impact on cancer growth. Taken
together, our findings implicate that LL-37 could attenuate the
development of pancreatic cancer by suppressing autophagy and
reprogramming of the tumor immune microenvironment.
Original language | English |
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Article number | 906625 |
Number of pages | 16 |
Journal | Frontiers in Pharmacology |
Volume | 13 |
DOIs | |
Publication status | Published - 22 Jul 2022 |
User-Defined Keywords
- autophagy
- LL-37
- mTOR signaling
- pancreatic cancer
- ROS
- tumor immune microenvironment