Original Article Constitutive activation with overexpression of the mTORC2-phospholipase D1 pathway in uterine leiomyosarcoma and STUMP: Morphoproteomic analysis with therapeutic implications
Sadhna Dhingra, Michelle E Rodriguez, Qi Shen, Xuizhen Duan, Melissa L Stanton, Lei Chen, Rongzhen Zhang, Robert E. Brown
Department of Pathology and Laboratory Medicine, UT Health- Medical School at Houston, 6431 Fannin St, Houston, TX 77030, USA; Scott & White, 2401 S. 31st St. Temple, TX 76508, USA; Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Received January 24, 2011; accepted January 26, 2010; Epub January 28, 2010; published February 15, 2011
Abstract: The mammalian target of rapamycin (mTOR) is centrally involved in growth, survival and metabolism. In cancer, mTOR is frequently hyperactivated and is a clinically validated target for therapy and drug development. Biologically, mTOR acts as the catalytic subunit of two functionally distinct complexes, called mTOR complex 1 (mTORC1) which is predominantly cytoplasmic in subcellular localization and mTOR complex 2 (mTORC2) which is both cytoplasmic and nuclear. mTORC1 is sensitive to the selective inhibitor rapamycin. By contrast, mTORC2 is relatively resistant to rapamycin. Moreover, its putative downstream effector, Akt phosphorylated on serine 473 represents a signal transduction pathway for tumor survival. Phospholipase D (PLD) and its product, phosphatidic acid (PA) have been implicated as an activator of mTOR signaling, including the direct phosphorylative activation of p70S6K at threonine 389. The latter promotes cell cycle progression. In this study, we investigated the activation status and subcellular localization of mTOR and the relative expression of PLD1, as well as their downstream effectors in a spectrum of uterine smooth muscle tumors using normal myometria as controls. The results show significant activation with overexpression of phosphorylated mTORC2 complex in uterine leiomyosarcoma (ULMS) and smooth muscle tumors of uncertain malignant potential (STUMP) as evidenced by nuclear localization of p-mTOR (Ser 2448)in ULMS>STUMP>uterine leiomyoma and normal myometria (p<0.05) and with overexpression of PLD1(p<0.05) . Correlatively, there are overexpressions of nuclear p-Akt (Ser 473) and nuclear p-p70S6K (Thr 389) in ULMS and STUMP (p<0.05). The activation with overexpression of components of the mTORC2-PLD1 pathway in ULMS and to a lesser degree in STUMP provides insight into their tumorigenic mechanisms. Thus the development of therapies designed to target mTORC2 and PLD1 activity may be beneficial in treating ULMS. (IJCEP1101007).
Address all correspondence to: Robert E. Brown, M.D. Department of Pathology and Laboratory Medicine University of Texas Health Science Center Medical School at Houston 6431 Fannin Street, MSB 2.286 Houston, TX 77030 Tel: 713-500-5332 Fax: 713-500-0695 E-mail: Robert.Brown@uth.tmc.edu