Pin1 inhibition exerts potent activity against acute myeloid leukemia through blocking multiple cancer-driving pathways

Abstract

BackgroundThe 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.MethodsThe 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.ResultsFirst, 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.ConclusionsWe demonstrate that Pin1 is highly overexpressed in human AML and is a promising therapeutic target to block multiple cancer-driving pathways in AML.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0611-7) contains supplementary material, which is available to authorized users.

Targeting PIN1 exerts potent antitumor activity in pancreatic ductal carcinoma via inhibiting tumor metastasis

“…Traditional prognostic tools and common therapeutic targets have not achieved satisfactory results in clinical studies of high intratumor heterogeneity in PDAC . Targeting PIN1, to block multiple signaling pathways, has been demonstrated to exhibit potent antitumor effects in tumors with poor prognosis but limited therapeutic efficiency in clinical practice . As for the devastating disease of PDAC, our present study indicated that PIN1 may be an attractive predictive marker and targeting PIN1 could exert potent antitumor activity.…”

“…Given that Pin1−/− homozygous mice grow normally and there are no general side effects on normal cells, PIN1 is a potential molecular target for cancer treatment. Notably, targeting of PIN1 has been achieving some promising results in animal studies on leukemia, triple negative breast cancer and hepatocellular carcinoma . However, little evidence on the function of PIN1 in the progression of PDAC has been seen.…”

Pin1 inhibition potently suppresses gastric cancer growth and blocks PI3K/AKT and Wnt/β‐catenin oncogenic pathways

“…ATRA binds and induces degradation of Pin1 and its substrate PML‐RARA and thereby exerts anticancer activity against APL in cell and animal models and human patients . This anticancer activity of ATRA has been confirmed and expanded to breast cancer, liver cancer even using a different ATRA controlled release formulation, and acute myeloid leukemia (AML), as well as in lupus and asthma . However, the role of Pin1 in mediating ATRA anticancer activity against gastric cancer is not known.…”

Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells

“…ATRA-induced Pin1 ablation also exerts antitumor activity against breast cancer by blocking multiple oncogenic pathways. The ability of ATRA to inhibit Pin1 function has been confirmed in breast cancer 24 , 39 and liver cancer 24 , 40 , 41 even using a different ATRA controlled release formulation 42 , and acute myeloid leukemia (AML) 43 , as well as in lupus 44 and asthma 45 . However, regular ATRA formulation has a half-life of only 45 min in humans 46 and biodegrabable longer half-life of ATRA formulations that might be used in humans are under development 42 .…”