PTBP3 promotes malignancy and hypoxia‐induced chemoresistance in pancreatic cancer cells by ATG12 up‐regulation

Abstract

Pancreatic ductal adenocarcinoma (PDAC) tumours exhibit a high level of heterogeneity which is associated with hypoxia and strong resistance to chemotherapy. The RNA splicing protein polypyrimidine tract‐binding protein 3 (PTBP3) regulates hypoxic gene expression by selectively binding to hypoxia‐regulated transcripts. We have investigated the role of PTBP3 in tumour development and chemotherapeutic resistance in human PDAC tissues and pancreatic cancer cells. In addition, we determined the sensitivity of cancer cells to gemcitabine with differential levels of PTBP3 and whether autophagy and hypoxia affect gemcitabine resistance in vitro. PTBP3 expression was higher in human pancreatic cancer than in paired adjacent tissues. PTBP3 overexpression promoted PDAC proliferation in vitro and tumour growth in vivo, whereas PTBP3 depletion had opposing effects. Hypoxia significantly increased the expression of PTBP3 in pancreatic cancer cells in vitro. Under hypoxic conditions, cells were more resistance to gemcitabine. Knockdown of PTBP3 results in decreased resistance to gemcitabine, which was attributed to attenuated autophagy. We propose that PTBP3 binds to multiple sites in the 3′‐UTR of ATG12 resulting in overexpression. PTBP3 increases cancer cell proliferation and autophagic flux in response to hypoxic stress, which contributes to gemcitabine resistance.

RNA Binding Proteins as Drivers and Therapeutic Target Candidates in Pancreatic Ductal Adenocarcinoma

“…For this study, we focused on the PoRs (Figure 3A), since these represent factors that may promote dedifferentiation and diseases progression and may thus present therapeutic targets eligible for treatment by inhibition, as proposed for LIN28B [29] and other RBPs. Among the 44 PoRs were proteins previously implicated in PDAC progression, e.g., IGF2BP1-3 [13][14][15][16][17], IFIT3 [30], EXO1 [21], or PTBP3 [23]. However, there were also proteins that, to the best of our knowledge, have not yet been associated with oncogenic potential in pancreatic cancer, e.g., OAS proteins, RBM34 or DQX1.…”

“…Intriguingly, IGF2BP1, LIN28B, and HMGA2 form a self-promoting network antagonizing the tumor-suppressive actions of the let-7 miRNA family [20]. Other RBPs with suggested tumor-promoting roles in PDAC include the 5'-3' exonuclease EXO1 [21] and the RBPs HuR (ELAVL1) and PTBP3, which both have been reported to lead to hypoxia-induced chemoresistance in pancreatic cancer cells [22,23].…”

Targeting hypoxic tumor microenvironment in pancreatic cancer

“…The RNA splicing protein polypyrimidine tract-binding protein 3 (PTBP3) is overexpressed in PDAC and promotes autophagy in response to hypoxic stress. It upregulates the expression of ATG12 post-transcriptionally by selectively binding to CU-rich elements in the 3′-untranslated regions (3′-UTR) of ATG12, thereby contributing to hypoxia-induced autophagy and gemcitabine resistance [ 99 ]. Moreover, hypoxia-mediated ROS production inhibits Akt/mTORC1 pathway to induce autophagy in PC [ 100 ].…”

Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo

“…The expression of LC3 and p62 has been reported to mark active autophagy in pancreatic ductal adenocarcinoma (PDAC). In pancreatic cancer cells, the lysosome-mediated degradation mechanism of autophagy is a pro-survival pathway in cancers [19] which frequently prospers under hypoxic conditions [27,28], likely facilitating chronically active autophagy which aids in tumor progression, chemoresistance, and metastasis [20,27,[29][30][31]. Through unconventional use of echinomycin, an antibiotic with activity against Listeria monocytogenes and Shigella dysenteriae that propagate inside autophagosomes [32,33], we assess the potential of echinomycin to result in autophagic cell death in apoptotic-resistant pancreatic cancer.…”