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Int J Clin Exp Pathol 2011;4(2):134-146

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).

Keywords: Morphoproteomics, mTORC2, phospholipase D1, uterine leiomyosarcoma, STUMP.

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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