miR-421 up-regulation by the oleanolic acid derivative K73-03 regulates epigenetically SPINK1 transcription in pancreatic cancer cells leading to metabolic changes and enhanced apoptosis

miR-421 up-regulation by the oleanolic acid derivative K73-03 regulates epigenetically SPINK1 transcription in pancreatic cancer cells leading to metabolic changes and enhanced apoptosis

[Display omitted] •MiR-421 expression in pancreatic cancer is lower than in the normal.•MiR-421 has correlation with SPINK1 and miR-421 modulates the SPINK1 transcription.•SPINK1 play vital role to improve the mitochondrial function and ATP synthesis.•K73-03 can induce mitochondrial damage, apoptosi...

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Published in:Pharmacological research Vol. 161; p. 105130
Main Authors: Shopit, Abdullah, Li, Xiaodong, Tang, Zhongyuan, Awsh, Mohammed, Shobet, Loubna, Niu, Mengyue, Wang, Hongyan, Mousa, Haithm, Alshwmi, Mohammed, Tesfaldet, Tsehaye, Gamallat, Yaser, Li, Hailong, Chu, Peng, Ahmad, Nisar, Jamalat, Yazeed, Ai, Jie, Qaed, Eskandar, Almoiliqy, Marwan, Wang, Shisheng, Tang, Zeyao
Format: Journal Article
Language:English
Published: Netherlands Elsevier Ltd 01-11-2020
Subjects:
Gemcitabine
K73-03
miR-421
Oleanolic acid
Pancreatic cancer
SPINK1
Oleanolic acid (PubChem CID: 10494)
SPINK1
Gemcitabine
GCB
FCCP
MAPK
ATCC
SASP
TME
EGFR
Oleanolic acid
miR-421
OA
PDAC
K73-03
Gemcitabine (PubChem CID: 60749)
ANOVA
Pancreatic cancer
MMP (ΔΨm)
ROX
EZH2
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Summary:[Display omitted] •MiR-421 expression in pancreatic cancer is lower than in the normal.•MiR-421 has correlation with SPINK1 and miR-421 modulates the SPINK1 transcription.•SPINK1 play vital role to improve the mitochondrial function and ATP synthesis.•K73-03 can induce mitochondrial damage, apoptosis and autophagy in the AsPC-1 cells.•K73-03 can up-regulate miR-421 and down-regulate SPINK1 expressions in-vitro and in-vivo. SPINK1 overexpression promotes cancer cell aggressiveness and confers chemo-resistance to multiple drugs in pancreatic cancer. Oleanolic acid (OA) derivatives possess active effects against different cancers. Here we report the effect of K73-03, a new novel OA derivative, against pancreatic cancer through mitochondrial dysfunction via miR-421/SPINK1 regulation. We examined the binding ability of miR-421 with SPINK1-3’UTR Luciferase reporter assays. Moreover, miR-421/SPINK1 expressions in pancreatic cancer, with or without K73-03 treatment, were evaluated. Cells viability, migration, autophagy, mitochondrial function and apoptosis were examined with or without K73-03 treatment. We established that the K73-03 effect on the miR-421 that plays a crucial role in the regulation of SPINK1 in pancreatic cancer. Our findings indicated that K73-03 inhibited the mitochondrial function that led to inducing autophagy and apoptosis through epigenetic SPINK1 down-regulation via miR-421 up-regulation in pancreatic cancer. Furthermore, the inhibition of miR-421 expression in pancreatic cancer cells abolished the efficacy of K73-03 against SPINK1 oncogenic properties. We found an interesting finding that the interaction between miR-421 and SPINK1 is related to mitochondrial function through the effect of K73-03. Further, SPINK1 appear to be the molecular targets of K73-03 especially more than gemcitabine.
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ISSN:1043-6618
1096-1186
DOI:10.1016/j.phrs.2020.105130