Garcia-Bates Tatiana M, Bernstein Steven H, Phipps Richard P
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Clin Cancer Res. 2008 Oct 15;14(20):6414-25. doi: 10.1158/1078-0432.CCR-08-0457.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a transcription factor that regulates immune and inflammatory responses. Our laboratory has shown that normal and malignant B cells, including multiple myeloma, express PPARgamma. Moreover, certain PPARgamma ligands can induce apoptosis in multiple myeloma cells. Because PPARgamma ligands can also have PPARgamma-independent effects, the role of PPARgamma in B-cell malignancies remains poorly understood. To further understand the role of PPARgamma, we examined the functional consequences of its overexpression in human multiple myeloma.
In the present work, we developed a lentiviral vector for PPARgamma gene delivery. We transduced multiple myeloma cells with a lentivirus-expressing PPARgamma and studied the involvement of this receptor on cell growth and viability.
PPARgamma overexpression decreased multiple myeloma cell proliferation and induced spontaneous apoptosis even in the absence of exogenous ligand. These PPARgamma-overexpressing cells were dramatically more sensitive to PPARgamma ligand-induced apoptosis compared with uninfected or LV-empty-infected cells. Apoptosis was associated with the down-regulation of antiapoptotic proteins X-linked inhibitor of apoptosis protein and myeloid cell leukemia-1 as well as induction of caspase-3 activity. Importantly, PPARgamma overexpression-induced cell death was not abrogated by coincubation with bone marrow stromal cells (BMSC), which are known to protect multiple myeloma cells from apoptosis. Additionally, PPARgamma overexpression in multiple myeloma or BMSC inhibited both basal and multiple myeloma-induced interleukin-6 production by BMSC.
Our results indicate that PPARgamma negatively controls multiple myeloma growth and viability in part through inhibition of interleukin-6 production by BMSC. As such, PPARgamma is a viable therapeutic target in multiple myeloma.
过氧化物酶体增殖物激活受体γ（PPARγ）是一种调节免疫和炎症反应的转录因子。我们实验室已表明，包括多发性骨髓瘤在内的正常和恶性B细胞均表达PPARγ。此外，某些PPARγ配体可诱导多发性骨髓瘤细胞凋亡。由于PPARγ配体也可能具有不依赖PPARγ的效应，因此PPARγ在B细胞恶性肿瘤中的作用仍知之甚少。为了进一步了解PPARγ的作用，我们研究了其在人多发性骨髓瘤中过表达的功能后果。
在本研究中，我们构建了一种用于PPARγ基因传递的慢病毒载体。我们用表达PPARγ的慢病毒转导多发性骨髓瘤细胞，并研究该受体在细胞生长和存活中的作用。
即使在没有外源性配体的情况下，PPARγ过表达也会降低多发性骨髓瘤细胞的增殖并诱导自发凋亡。与未感染或感染空载体的细胞相比，这些过表达PPARγ的细胞对PPARγ配体诱导的凋亡显著更敏感。凋亡与抗凋亡蛋白X连锁凋亡抑制蛋白和髓样细胞白血病-1的下调以及半胱天冬酶-3活性的诱导有关。重要的是，与已知可保护多发性骨髓瘤细胞免于凋亡的骨髓基质细胞（BMSC）共同孵育并不能消除PPARγ过表达诱导的细胞死亡。此外，多发性骨髓瘤细胞或BMSC中PPARγ的过表达抑制了BMSC的基础和多发性骨髓瘤诱导的白细胞介素-6产生。
我们的结果表明，PPARγ部分通过抑制BMSC产生白细胞介素-6来负向控制多发性骨髓瘤的生长和存活。因此，PPARγ是多发性骨髓瘤中一个可行的治疗靶点。
