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Pin1 inhibition exerts potent activity against acute myeloid leukemia through blocking multiple cancer-driving
Xiaolan Lian1,2,3, Yu-Min Lin2, Shingo Kozono2
1Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China.
Background:
The increasing genomic complexity of acute myeloid leukemia (AML), the most common form of acute leukemia, poses a major challenge to its therapy. To identify potent therapeutic targets with the ability to block multiple cancer-driving pathways is thus imperative. The unique peptidyl-prolyl cis-trans isomerase Pin1 has been reported to promote tumorigenesis through upregulation of numerous cancer-driving pathways. Although Pin1 is a key drug target for treating acute promyelocytic leukemia (APL) caused by a fusion oncogene, much less is known about the role of Pin1 in other heterogeneous leukemia.
Methods:
The mRNA and protein levels of Pin1 were detected in samples from de novo leukemia patients and healthy controls using real-time quantitative RT-PCR (qRT-PCR) and western blot. The establishment of the lentiviral stable-expressed short hairpin RNA (shRNA) system and the tetracycline-inducible shRNA system for targeting Pin1 were used to analyze the biological function of Pin1 in AML cells. The expression of cancer-related Pin1 downstream oncoproteins in shPin1 (Pin1 knockdown) and Pin1 inhibitor all-trans retinoic acid (ATRA) treated leukemia cells were examined by western blot, followed by evaluating the effects of genetic and chemical inhibition of Pin1 in leukemia cells on transformed phenotype, including cell proliferation and colony formation ability, using trypan blue, cell counting assay, and colony formation assay in vitro, as well as the tumorigenesis ability using in vivo xenograft mouse models.
Results:
First, we found that the expression of Pin1 mRNA and protein was significantly increased in both de novo leukemia clinical samples and multiple leukemia cell lines, compared with healthy controls. Furthermore, genetic or chemical inhibition of Pin1 in human multiple leukemia cell lines potently inhibited multiple Pin1 substrate oncoproteins and effectively suppressed leukemia cell proliferation and colony formation ability in cell culture models in vitro. Moreover, tetracycline-inducible Pin1 knockdown and slow-releasing ATRA potently inhibited tumorigenicity of U937 and HL-60 leukemia cells in xenograft mouse models.
Conclusions:
We demonstrate that Pin1 is highly overexpressed in human AML and is a promising therapeutic target to block multiple cancer-driving pathways in AML.
Insights
Pin1 is overexpressed in acute myeloid leukemia (AML), driving cancer pathways. Inhibiting Pin1, a peptidyl-prolyl cis-trans isomerase, suppressed leukemia cell growth and tumor formation, identifying it as a promising therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Acute myeloid leukemia (AML) presents genomic complexity, challenging effective therapy.
- Identifying therapeutic targets that inhibit multiple cancer-driving pathways is crucial for AML treatment.
- The peptidyl-prolyl cis-trans isomerase Pin1 promotes tumorigenesis and is a known target in acute promyelocytic leukemia (APL), but its role in other leukemias is less understood.
Purpose of the Study:
- To investigate the role of Pin1 in acute myeloid leukemia (AML).
- To evaluate Pin1 as a potential therapeutic target for blocking multiple cancer-driving pathways in AML.
Main Methods:
- Assessed Pin1 mRNA and protein levels in patient samples and cell lines using qRT-PCR and western blot.
- Utilized lentiviral and tetracycline-inducible short hairpin RNA (shRNA) systems for Pin1 knockdown.
- Examined downstream oncoproteins and evaluated cellular proliferation, colony formation, and tumorigenicity in vitro and in vivo models following Pin1 inhibition.
Main Results:
- Pin1 mRNA and protein expression were significantly elevated in de novo leukemia samples and cell lines compared to controls.
- Genetic or chemical inhibition of Pin1 suppressed key oncoproteins and reduced leukemia cell proliferation and colony formation in vitro.
- In vivo studies demonstrated that Pin1 inhibition effectively reduced the tumorigenicity of AML cells in mouse models.
Conclusions:
- Pin1 is highly overexpressed in human AML.
- Pin1 represents a promising therapeutic target for blocking multiple cancer-driving pathways in AML.
- Targeting Pin1 offers a potential strategy for novel AML therapies.
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