Overexpression of Phospholipase D1 in Prostatic Adenocarcinoma: Pathogenetic and Therapeutic Implications
B Zhao, RE Brown. University of Texas - Medical School, Houston, TX
Background: Phospholipase D1 (PLD1) catalyzes the conversion of phosphatidylcholine to form phosphatidic acid (PA). Both PLD1 and PA are involved in the signaling by mammalian target of rapamycin complex1 (mTORC1) and in addition, PA, per se has been shown to bind to and phosphorylate p70S6K at threonine 389 . In light of this, and because we had previously demonstrated the expression of constitutively activated p-mTOR (Ser 2448) in the plasmalemmal and/or cytoplasmic compartments of prostatic adenocarcinoma (PAC) accompanied by the constitutive activation with nuclear translocation of p70S6K phosphorylated on threonine 389, we postulated that PLD1 may be a factor in such constitutive activation of mTOR and p70S6K analytes in PAC.
Design: Tissue microarrays containing 37 cases of PAC and 24 cases on non-neoplastic prostatic tissue were included in the study. An immunohistochemical probe for PLD1 (PC-PLD1 [sc-28314], Santa Cruz Biotechnology, Inc., Santa Cruz, CA) was applied to representative sections of each using a standard diaminobenzidine chromogen detection system. An automated cellular imaging system (ACIS III, DAKO Corporation, Carpinteria, CA) was employed, and gating of representative areas was carried out by one of us (BZ).The threshold was set to assess the percentage of immunopositive pixels and scoring intensity of the gated areas. The total staining score of the cells with immunopositivity was generated from the product of the two measured parameters. A mean total score of PLD 1 expression with standard deviation (SD) was generated for each subset. Statistical analysis was carried out using the student t-test.
Results: PLD1 total expression scores in the cytoplasmic/plasmalemmal and nucleolar compartments from each of the subsets were as follows: PAC (4572 +/-2109) versus non-neoplastic/BPH glandular epithelium (1052+/-879). Statistically, this revealed PLD1 expression to be significantly greater in PAC versus the non-neoplastic subset (p=1.55x10-10).
Conclusions: PLD1 is overexpressed in prostatic adenocarcinoma. This coincides with our previous observation concerning the constitutive activation of p-mTOR (Ser 2448) and p-p70S6K (Thr 389) in PAC. Activation of this mitogenic pathway has pathogenetic implications for the progression of PAC. Therefore, agents that could interfere in PLD1-PA-mTORC1-PA-p70S6K signaling such as curcumin, triptolide and metformin offer preventive and therapeutic opportunities in retarding the progression of prostate cancer and warrant further investigation.
Category: Genitourinary (including renal tumors)
Wednesday, March 24, 2010 9:30 AM
Poster Session V # 98, Wednesday Morning