Metastasis regulation by PPARD expression in cancer cells

Zuo

et al. 2019

Preprint

Self Cite

Aberrant Wnt/β-catenin activation is a major driver of colorectal cancer (CRC), which is typically initiated by APC mutations. Additional modifiable factors beyond APC mutations have been recognized to be important for further potentiation of aberrant β-catenin activation to promote colorectal tumorigenesis. These factors have yet to be clearly identified. Western-type diets are increasingly enriched in linoleic acid (LA). LA-enriched diet however promotes chemically-induced colorectal tumorigenesis in rodent models. Furthermore, the main metabolizing enzyme of LA, 15-lipoxygenase-1 (15-LOX-1), is transcriptionally silenced in CRC. Whether LA and 15-LOX-1 affect Wnt/β-catenin signaling to modulate colorectal tumorigenesis is poorly understood. Herein, we report that high dietary LA promoted colorectal tumorigenesis in mice with intestinally targeted APC mutation (Apc Δ580 ) by upregulating a Wnt receptor, LRP5 expression, and β-catenin activation. 15-LOX-1 transgenic expression in intestinal epithelial cells suppressed LRP5 expression, β-catenin activation and subsequently CRC in these mice. In particular, 15-LOX-1 peroxidation of LA in phosphatidylinositol-3-phosphates (PI3P_LA) into PI3P_13-HODE decreased PI3P binding to SNX17and LRP5, which inhibited LRP5 recycling from endosomes to the plasma membrane, thereby leading to an increase of LRP5 lysosomal degradation. Our findings demonstrate for the first time that 15-LOX-1 metabolism of LA in PI3P to regulate LRP5 membrane abundance is a modifiable factor of Wnt/β-catenin aberrant signaling that could be potentially therapeutically targeted to suppress colorectal tumorigenesis and progression.

Section: Immunohistochemical Analysismentioning

confidence: 99%

“…Western blot was performed as described previously (Zuo et al, 2017). Briefly, the cultured cells or the IECs scraped from the mice colons were lysed in the lysis buffer (Zuo et al, 2017) with sonication in ice water. The blots were probed with primary and secondary antibodies.…”

Section: Western Blotmentioning

confidence: 99%

Suppression of membranous LRP5 recycling, WNT/β-catenin signaling, and colorectal tumorigenesis by 15-LOX-1 peroxidation of PI3P_linoleic acid

Zuo

et al. 2019

Preprint

Self Cite

“…To determine the molecular mechanisms by which PPARD enhanced β -catenin activation, we used comparative transcriptome profile analyses (RNA sequencing) of HCT-116-WT and KO1 (HCT-116 PPARD KO) cells (9). These analyses revealed that bone morphogenetic protein 7 (BMP7) mRNA expression was 11-fold higher in WT cells than in KO1 cells ( Supplementary Fig.…”

Section: β -Catenin Via Bmp7/tak1 Signaling In Iecsmentioning

confidence: 99%

“…Germline KO of PPARD in Apc min mouse models produced contradictory results (11,12). PPARD is, however, overexpressed in IECs of human CRC (6)(7)(8)(9). We therefore sought to test the effects of PPARD overexpression in IECs of APC-mutant mice.…”

Section: Ppard Accelerates Apc Mutation-driven Intestinal Tumorigenesismentioning

confidence: 99%

“…The ligand-activated nuclear receptor peroxisome proliferator-activated receptor-δ/β (PPARD) has pleiotropic effects on cell homeostasis (5). PPARD is upregulated in human colorectal polyps and CRC (6)(7)(8)(9)and has been identified as a downstream target of the β -catenin/TCF4 complex in CRC cell lines (6). However, this proposed mechanistic link between β -catenin and PPARD has been questioned on the basis of in vitro and in vivo data (10).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pleotropic effects of PPARD accelerate colorectal tumor progression and invasion

Deguchi

Tian

et al. 2018

Preprint

Self Cite

Synergistic effects of PI3K inhibition and pioglitazone against acute promyelocytic leukemia cells

Esmaeili

Yousefi

Delshad

et al. 2022

Molec Gen & Gen Med

Background Although pioglitazone, a well‐known anti‐diabetic agent, has recently established itself as a pillar of cancer treatment, its therapeutic value could be attenuated by the aberrant activation of the PI3K/Akt pathway. Aim To evaluate whether the PI3K/Akt suppression in leukemic cells could potentiate the anti‐leukemic effects of pioglitazone. Methods To assess the anti‐leukemic effects of PI3K/Akt inhibitors on anti‐leukemic effects of pioglitazone, we used MTT and trypan blue assays. Flow cytometric analysis and qRT‐PCR were also applied to evaluate cell cycle and apoptosis. Result The resulting data revealed that upon PPARγ stimulation in different leukemic cell lines using pioglitazone, the survival and the proliferative capacity of the cells were significantly halted. Then, we evaluated the impact of the PI3K/Akt axis on the effectiveness of the drug in the most sensitive leukemic cell line; NB4 cells. Our results showed that treatment of NB4 cells with the PI3K inhibitors increased the sensitivity of leukemic cells to pioglitazone to the degree that even lower concentrations of the agent succeeded to induce apoptotic as well as the anti‐proliferative effects. Moreover, it seems that PI3K inhibition could potentiate the anti‐leukemic effect of pioglitazone through induction of p21‐mediated sub‐G1 cell cycle arrest and altering the balance between the pro‐and anti‐apoptotic genes. Conclusion This study sheds light on the significance of the PI3K/Akt pathway in APL cell sensitivity to pioglitazone and proposed that the presence of the PI3K inhibitor in the therapeutic regimen containing pioglitazone could be promising in the treatment of this malignancy.