Inhibition of tumorigenesis by peroxisome proliferator-activated receptor (PPAR)-dependent cell cycle blocks in human skin carcinoma cells

Abstract

To examine the functional role of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) and PPARγ in skin cancer, stable cell lines were created in the A431 human squamous cell carcinoma cell line. Expression of PPAR target genes was greatly enhanced in response to ligand activation of PPARβ/δ or PPARγ in A431 cells expressing these receptors. PPARβ/δ expression blocked the cell cycle at the G2/M phase, and this effect was increased by ligand activation. Ligand activation of PPARβ/δ markedly inhibited clonogenicity as compared to vehicle-treated controls. Similarly, ligand activation of PPARγ in A431 cells expressing PPARγ resulted in reduced clonogenicity. Expression of either PPARβ/δ or PPARγ markedly reduced tumor volume in ectopic xenografts, while ligand activation of these receptors had little further influence on tumor volume. Collectively, these studies demonstrate that stable expression and activation of PPARβ/δ or PPARγ in A431 cells led to reduced tumorigenicity. Importantly, PPAR expression or ligand activation had major impacts on clonogenicity and/or tumor volume. Thus, PPARβ/δ or PPARγ could be therapeutically targeted for the treatment of squamous cell carcinomas.

Regulatory mechanisms mediated by peroxisome proliferator‐activated receptor‐β/δ in skin cancer

“…Because the latter study applied topical PPARβ/δ ligands postirradiation, the results from this study controlled for the sunscreen effect and provide a better degree of clarity than the former study that has multiple weaknesses. In addition, inhibition of ectopic xenograft growth from A431 SCC cell line over‐expressing PPARβ/δ provide further evidence that PPARβ/δ can inhibit tumorigenesis of a human SCC cell line‐derived xenografts that contain mutant TP53 ; a signature mutation causally linked to UV‐induced skin carcinogenesis. Thus, there remains a need for more studies to determine the role of PPARβ/δ in UV‐induced non‐melanoma skin cancer because results obtained from studies examining the effect of chemopreventive and chemotherapeutic agents in two‐chemical skin carcinogenesis models and xenograft studies are typically similar to those observed in UV‐induced skin cancer models.…”

“…The role of PPARβ/δ has also been examined using A431 cells, a human SCC cell line with mutant EGFR and TP53 (the latter a common mutation observed in UV light‐induced non‐melanoma skin cancer). The growth of ectopic xenografts derived from stable A431 cells overexpressing PPARβ/δ was markedly inhibited and essentially negligible as compared to controls A431 cells . Interestingly, ligand activation of PPARβ/δ with GW0742 did not further influence this striking inhibition .…”

“…Results from these studies also showed that ligand activation of PPARβ/δ targeted HRAS‐expressing keratinocytes as compared with controls, and selectively caused HRAS‐expressing keratinocytes to undergo a block in the G2/M phase of the cell cycle. This is interesting because the human SCC cell line A431 also exhibits a block in the G2/M phase of the cell cycle in response to ligand activation of PPARβ/δ with GW0742, since these cells are mutant for TP53 a common etiological factor in UV‐induced non‐melanoma skin cancer. More detailed analyses of HRAS‐expressing keratinocytes demonstrated that this was mediated by E2F crosstalk with PPARβ/δ.…”

“…Reference(s) Activation of PPARβ/δ causes increased terminal differentiation [25][26][27][28] Activation of PPARβ/δ causes inhibition of proliferation [28][29][30][31][32][33][34][35][36] PPARβ/δ modulates bioactivation of chemical carcinogens 37 Ligand activation of PPARβ/δ inhibits non-melanoma skin cancer 32,33,[38][39][40] Inhibition of non-melanoma skin cancer by PPARβ/δ mediated by enhanced terminal differentiation 32,33,39 Inhibition of non-melanoma skin cancer by PPARβ/δ mediated by a block in the G2/M phase of cell cycle 36,40 Inhibition of non-melanoma skin cancer by PPARβ/δ mediated by enhanced senescence 41 Inhibition of non-melanoma skin cancer by PPARβ/δ mediated by inhibition of ER stress 42 Inhibition of non-melanoma skin cancer by PPARβ/δ influenced by inhibition of proinflammatory signaling [29][30][31]38 Ligand activation of PPARβ/δ inhibits melanoma [43][44][45][46] Abbreviations: ER, endoplasmic reticulum; PPARβ/δ, peroxisome proliferator-activated receptor-β/δ. PETERS ET AL.…”

“…The growth of ectopic xenografts derived from stable A431 cells overexpressing PPARβ/δ was markedly inhibited and essentially negligible as compared to controls A431 cells. 40 Interestingly, ligand activation of PPARβ/δ with GW0742 did not further influence this striking inhibition. 40 These observations collectively provide the support that PPARβ/δ also inhibits human non-melanoma skin cancer associated with mutant TP53 and suggest that there are endogenous ligands for PPARβ/δ that may promote this phenotype in cells that exhibit relatively high expression of PPARβ/δ such as keratinocytes.…”