Abstract
Gemcitabine (GEM) is the first-line medication for pancreatic ductal adenocarcinoma
(PDAC). However, over some treatment cycles, GEM sensitivity declines and chemotherapeutic
resistance develops, resulting in tumor recurrence and metastasis. Therefore, it is
critical to elucidate the mechanism of GEM chemoresistance. And a specific drug that
is closely related to the mechanism is urgently required to sensitize GEM. Here, tissue
inhibitor of matrix metalloproteinases 1 (TIMP1) and phosphorylated mammalian target
of rapamycin (p-mTOR) were found to be substantially elevated in PDAC patients and
were associated with worse overall survival. The TIMP1/PI3K/AKT/mTOR pathway was found
in GEM-resistant PDAC cells and was revealed to be involved in epithelial-mesenchymal
transition (EMT) and apoptosis. Furthermore, arsenic trioxide (ATO), a basic therapeutic
drug for acute promyelocytic leukemia, mediated TIMP1 reduction by inducing reactive
oxygen species generation and hampered the subsequent PI3K/AKT/mTOR axis. Moreover,
the combination of ATO and GEM cooperatively suppressed the TIMP1/PI3K/AKT/mTOR pathway,
synergistically inhibited EMT and promoted apoptosis. In vitro and in vivo, ATO combined
with GEM has a collaborative anticancer effect, inhibiting cancer cell proliferation,
migration, invasion, and suppressing tumor growth both in PDAC parental and GEM-resistant
cells. Overall, the TIMP1/PI3K/AKT/mTOR pathway is present in PDAC and linked to GEM
resistance. ATO suppresses the axis to sensitize GEM and reverse GEM resistance, suggesting
a promising treatment for the disease.
Abbreviations:
ATO (Arsenic Trioxide), CI (Combined Index), DHE (Dihydroethidium), DMEM (Dulbecco's modified Eagle's medium), EMT (Epithelial-mesenchymal transition), GEM (Gemcitabine), HR (Hazard ratio), IHC (Immunohistochemistry), mTOR (Mammalian target of rapamycin), NAC (N-acetyl-L-cysteine), OS (Overall survival), PBS (Phosphate buffer solution), PDAC (Pancreatic ductal adenocarcinoma), p-mTOR (Phosphorylated mammalian target of rapamycin), qRT-PCR (Quantitative real time polymerase chainreaction), ROS (Reactive oxygen species), siRNA (Small interfering RNA), TIMP1 (Tissue inhibitor of matrix metalloproteinases 1)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Global, regional, and national cancer incidence and death for 29 cancer groups in 2019 and trends analysis of the global cancer burden, 1990-2019.J Hematol Oncol. 2021; 14: 197
- Pancreatic cancer: yesterday, today and tomorrow.Future Oncol. 2016; 12: 1929-1946
- Gemcitabine resistance in pancreatic ductal adenocarcinoma.Drug Resist Updat. 2015; 23: 55-68
- Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component.EMBO Mol Med. 2021; 13: e13502
- Akhavan-Niaki H. PI3K/AKT/mTOR signaling in gastric cancer: epigenetics and beyond.Life Sci. 2020; 262118513
- The PI3K/AKT pathway as a target for cancer treatment.Annu Rev Med. 2016; 67: 11-28
- Targeting the Akt/PI3K signaling pathway as a potential therapeutic strategy for the treatment of pancreatic cancer.Curr Med Chem. 2017; 24: 1321-1331
- Targeting apoptosis pathways in pancreatic cancer.Cancer Lett. 2013; 332: 346-358
- Timp1 interacts with beta-1 integrin and CD63 along melanoma genesis and confers anoikis resistance by activating PI3-K signaling pathway independently of Akt phosphorylation.Mol Cancer. 2013; 12: 22
- Gemcitabine-induced TIMP1 attenuates therapy response and promotes tumor growth and liver metastasis in pancreatic cancer.Cancer Res. 2017; 77: 5952-5962
- Pancreatic premalignant lesions secrete tissue inhibitor of metalloproteinases-1, which activates hepatic stellate cells via CD63 signaling to create a premetastatic niche in the liver.Gastroenterology. 2016; 151 (e7): 1011-1024
- TIMP1 down-regulation enhances gemcitabine sensitivity and reverses chemoresistance in pancreatic cancer.Biochem Pharmacol. 2021; 189114085
- Therapeutic strategy of arsenic trioxide in the fight against cancers and other diseases.Metallomics. 2020; 12: 326-336
- Arsenic trioxide inhibits Skp2 expression to increase chemosensitivity to gemcitabine in pancreatic cancer cells.Am J Transl Res. 2019; 11: 991-997
- Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosis using a nanomedicine strategy for the effective treatment of pancreatic cancer.Nanomedicine. 2014; 10: 463-472
- The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care.Expert Rev Anticancer Ther. 2018; 18: 775-784
- The SMART App: an interactive web application for comprehensive DNA methylation analysis and visualization.Epigenetics Chromatin. 2019; 12: 71
- Drug combination studies and their synergy quantification using the Chou-Talalay method.Cancer Res. 2010; 70: 440-446
- SH3BGRL2 inhibits growth and metastasis in clear cell renal cell carcinoma via activating hippo/TEAD1-Twist1 pathway.EBioMedicine. 2020; 51102596
- Quercetin facilitates cell death and chemosensitivity through RAGE/PI3K/AKT/mTOR axis in human pancreatic cancer cells.J Food Drug Anal. 2019; 27: 887-896
- Arsenic induced epigenetic changes and relevance to treatment of acute promyelocytic leukemia and beyond.Toxicol Appl Pharmacol. 2020; 406115212
- ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction underlie apoptosis induced by resveratrol and arsenic trioxide in A549 cells.Chem Biol Interact. 2016; 245: 100-109
- Inhibition of FEN1 increases arsenic trioxide-induced ROS accumulation and cell death: novel therapeutic potential for triple negative breast cancer.Front Oncol. 2020; 10: 425
- Vitamin E inhibits cyclosporin A-induced CTGF and TIMP-1 expression by repressing ROS-mediated activation of TGF-β/Smad signaling pathway in rat liver.Int Immunopharmacol. 2018; 65: 493-502
- KRAS mutant pancreatic cancer: no lone path to an effective treatment.Cancers (Basel). 2016; 8: 45
- Challenges in Ras therapeutics in pancreatic cancer.Semin Cancer Biol. 2019; 54: 101-108
- In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer.Int J Cancer. 2006; 118: 2337-2343
- siRNA therapeutics: a clinical reality.Sci China Life Sci. 2020; 63: 485-500
- The simpler, the better: oral arsenic for acute promyelocytic leukemia.Blood. 2019; 134: 597-605
- Arsenic trioxide inhibits EMT in hepatocellular carcinoma by promoting lncRNA MEG3 via PKM2.Biochem Biophys Res Commun. 2019; 513: 834-840
- The suppressive effect of arsenic trioxide on TET2-FOXP3-Lyn-Akt axis-modulated MCL1 expression induces apoptosis in human leukemia cells.Toxicol Appl Pharmacol. 2018; 358: 43-55
- Impact of arsenic trioxide in the treatment of acute promyelocytic leukemia.Leukemia. 2012; 26: 433-442
- Arsenic toxicity and potential mechanisms of action.Toxicol Lett. 2002; 133: 1-16
- Arsenic trioxide induces ROS activity and DNA damage, leading to G0/G1 extension in skin fibroblasts through the ATM-ATR-associated Chk pathway.Environ Sci Pollut Res Int. 2017; 24: 5316-5325
- Drug-induced mitochondrial dysfunction and cardiotoxicity.Am J Physiol Heart Circ Physiol. 2015; 309: H1453-H1467
- High glucose-induced oxidative stress mediates apoptosis and extracellular matrix metabolic imbalances possibly via p38 MAPK activation in rat nucleus pulposus cells.J Diabetes Res. 2016; 20163765173
Article info
Publication history
Published online: November 14, 2022
Accepted:
November 9,
2022
Received in revised form:
November 9,
2022
Received:
June 17,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.