PPARG-selective inverse agonists can suppress proliferation in PPARG-activated bladder cancer cells.

  • Major finding: PPARG-selective inverse agonists can suppress proliferation in PPARG-activated bladder cancer cells.

  • Mechanism: PPARG inverse agonists promote the interaction between PPARG and the NCOR2 corepressor.

  • Impact: PPARG may be a candidate therapeutic target in patients with bladder cancer.

In a subset of patients with bladder cancer the nuclear receptor gene PPARG is directly activated by amplification or mutation, and in another subset of patients PPARG is indirectly activated through mutation of its requisite heterodimeric partner RXRA. Based on these findings, Goldstein and colleagues hypothesized that PPARG has an oncogenic role in transitional epithelial cells to promote bladder cancer. Ectopic expression of bladder cancer mutants, PPARG p.T447M or RXRA p.S427F/Y, activated PPARG signaling in a bladder cancer cell line. The PPARG inverse agonists T0070907 and SR10221 were sufficient to suppress PPARG target gene expression in cell lines where it was activated, and RNA sequencing in an PPARG-amplified cell line revealed that PPARG inverse agonists had distinct effects from PPARG antagonists. Inverse agonists bind to the same constitutively active receptor as an agonist but produce the opposite pharmacologic response, in contrast to neutral antagonists. The PPARG-selective inverse agonists enhanced the interaction between PPARG and the NCOR2 corepressor, generating a repressive complex in bladder cancer cells. However, PPARG partial agonists and antagonists had little effect on NCOR2. PPARG inverse agonists suppressed proliferation in a panel of PPARG-activated bladder cancer cell lines, including those with PPARG amplification or RXRA p.S427F, whereas antagonists did not. Further, bladder cancer cell lines lacking PPARG activation were not sensitive to the inverse agonists. The dependency of PPARG-activated cells on PPARG expression was further confirmed by knocking out PPARG. PPARG deficiency reduced fitness in competition assays, suggesting a dependency on functional PPARG. Altogether, these findings reveal an oncogenic role for PPARG in bladder cancer and suggest the potential for therapeutic targeting of PPARG.

Goldstein JT, Berger AC, Shih J, Duke FF, Furst L, Kwiatkowski DJ, et al. Genomic activation of PPARG reveals a candidate therapeutic axis in bladder cancer. Cancer Res 2017 Sep 18 [Epub ahead of print].

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