Combinatorial library discovery of small molecule inhibitors of lung cancer proliferation and parathyroid hormone-related protein expression

Hastings, Randolph H.; Burton, Douglas W.; Nefzi, Adel; Montgrain, Philippe R.; Quintana, Rick; Deftos, Leonard J.

doi:10.4161/cbt.10.10.13374

Cited by 12 publications

(9 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously screened a library of compounds and identified several that are capable of inhibiting PTHrP expression and cell growth in lung cancer [62]. It would be of great clinical interest to extend these results to prostate cancer and to determine whether such drugs are also capable of blocking PTHrP-induced EMT and invasion.…”

Section: Discussionmentioning

confidence: 99%

Parathyroid Hormone Related-Protein Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer

et al. 2014

Self Cite

View full text Add to dashboard Cite

Parathyroid hormone-related protein (PTHrP) possesses a variety of physiological and developmental functions and is also known to facilitate the progression of many common cancers, notably their skeletal invasion, primarily by increasing bone resorption. The purpose of this study was to determine whether PTHrP could promote epithelial-to-mesenchymal transition (EMT), a process implicated in cancer stem cells that is critically involved in cancer invasion and metastasis. EMT was observed in DU 145 prostate cancer cells stably overexpressing either the 1-141 or 1-173 isoform of PTHrP, where there was upregulation of Snail and vimentin and downregulation of E-cadherin relative to parental DU 145. By contrast, the opposite effect was observed in PC-3 prostate cancer cells where high levels of PTHrP were knocked-down via lentiviral siRNA transduction. Increased tumor progression was observed in PTHrP-overexpressing DU 145 cells while decreased progression was observed in PTHrP-knockdown PC-3 cells. PTHrP-overexpressing DU 145 formed larger tumors when implanted orthoptopically into nude mice and in one case resulted in spinal metastasis, an effect not observed among mice injected with parental DU 145 cells. PTHrP-overexpressing DU 145 cells also caused significant bone destruction when injected into the tibiae of nude mice, while parental DU 145 cells caused little to no destruction of bone. Together, these results suggest that PTHrP may work through EMT to promote an aggressive and metastatic phenotype in prostate cancer, a pathway of importance in cancer stem cells. Thus, continued efforts to elucidate the pathways involved in PTHrP-induced EMT as well as to develop ways to specifically target PTHrP signaling may lead to more effective therapies for prostate cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Parathyroid Hormone Related-Protein Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Moreover, anti-apoptotic effects of PTHrP (1–34) and (140–173) on BEN cells have been reported [26] and could contribute to lung cancer progression. Interestingly, Hastings and coworkers [27] have also documented that cyclic thiourea compounds inhibit PTHrP expression mediated by the P3 promoter in BEN cells and that they may inhibit growth of lung cancer cells through the same mechanism. A patient population study [28] reported the longer survival of women affected with PTHrP-secreting lung carcinomas; in addition, more recently Monego and collaborators [29] showed that the expression of both PTHrP (1–34) and PTH1R are independent prognostic markers of a worse clinical outcome in lung adenocarcinoma patients.…”

Section: Pthrp As An Anti-proliferative and Death-promoting Factormentioning

confidence: 99%

Parathyroid Hormone-Related Protein (PTHrP): A Key Regulator of Life/Death Decisions by Tumor Cells with Potential Clinical Applications

Luparello

2011

Cancers

View full text Add to dashboard Cite

Parathyroid hormone-related protein (PTHrP), classically regarded as the mediator of the humoral hypercalcemia of malignancy syndrome, is a polyhormone that undergoes proteolytic processing into smaller bioactive forms. These bioactive forms comprise an N-terminal-as well as midregion-and C-terminal peptides, which have been shown to regulate various biological events, such as survival, proliferation and differentiation, in diverse cell model systems, both normal and pathological. A number of experimental data have demonstrated that PTHrP is also able to modulate tumor-relevant phenotypic expressions, thereby playing a role in early and advanced tumorigenesis, and in the response to treatment. In particular, interest has mainly been focused on the effects of PTHrP on cell proliferation/apoptosis, migration and invasion, which are the main roles involved in cancer development in vivo. The objective of this review is to discuss collectively the literature data on the molecular and biochemical basis of the mechanisms underlying the different, and sometimes opposite, effects exerted by PTHrP on various neoplastic cytotypes, with some final comments on both present and potential utilization of PTHrP as a target for anti-cancer therapy.

show abstract

“…Also the protein has been implicated in cell growth, apoptosis and invasion [16–19]. Thus, increased Pthlh by ablation of Pparg may change the fetal lung architecture.…”

Section: Resultsmentioning

confidence: 99%

Lack of epithelial PPARγ causes cystic adenomatoid malformations in mouse fetal lung

Kim

Yamaori

Tanabe

et al. 2017

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptor-γ (PPARγ) plays an important role in lipid and glucose metabolism. In this study, the function of PPARγ on lung development was investigated. Lung-specific Pparg conditional knockout mice (PpargΔLuEpC) were developed using Cre-Lox system. PpargΔLuEpC mice showed abnormal lung development with enlarged airspaces and followed by increase of apoptotic cells at E14.5 to E18.5. Gene analysis revealed that expression of Pmaip1, a gene related to apoptosis, was significantly increased while expression of Retnla, a gene related to anti-apoptosis, was dramatically decreased in the fetal lung (E14.5) of PpargΔLuEpC mice. In addition, expression of Pthlh, a gene pheno-typically expressed in the congenital cystic adenomatoid malformation (CCAM), was increased at E14.5 to E18.5 in the lung of PpargΔLuEpC mice. Cell culture studies revealed that PPARγ could bind to promoter region of Pthlh gene as a repressor in the immortalized mouse lung epithelial cell line MLE-15. Surprisingly, phenotypic changes in MLE-15-shPparg cells, stably transfected with shPparg plasmid, were similar to the PpargΔLuEpC mice model. In addition, MLE-15-shPparg cells were easily detached from the cultured plate when cold phosphate buffered saline was applied. Furthermore, expression of Cdh1, a gene related to cell adhesion, was significantly reduced in the MLE-15-shPparg cells. Taken together, PPARγ may play an important role in fetal lung development via alveolar cell-to-cell adhesion system.

show abstract

Combinatorial library discovery of small molecule inhibitors of lung cancer proliferation and parathyroid hormone-related protein expression

Cited by 12 publications

References 18 publications

Parathyroid Hormone Related-Protein Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer

Parathyroid Hormone Related-Protein Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer

Parathyroid Hormone-Related Protein (PTHrP): A Key Regulator of Life/Death Decisions by Tumor Cells with Potential Clinical Applications

Lack of epithelial PPARγ causes cystic adenomatoid malformations in mouse fetal lung

Contact Info

Product

Resources

About