Secreted protein acidic and rich in cysteine as a regulator of murine cancer growth and chemosensitivity

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8593, USA.
American journal of obstetrics and gynecology (Impact Factor: 4.7). 12/2008; 200(2):180.e1-7. DOI: 10.1016/j.ajog.2008.08.047
Source: PubMed


Secreted protein acidic and rich in cysteine (SPARC) influences the growth of several solid tumors. Our objectives were to determine the effect of SPARC on the growth and response to cisplatin therapy of platinum-resistant ovarian cancer.
SPARC expression was determined in 4 platinum-resistant ovarian cancer cell lines. The effect of increasing SPARC on cell proliferation was determined in vitro. The effect of host-derived SPARC on tumor growth and response to therapy was determined in vivo using the murine ovarian cancer cell line, OSEID8, which was injected into the peritoneum of wild-type (WT) and SPARC-null (SP-/-) mice.
Forced expression of SPARC decreased growth of platinum-resistant ovarian cancer cell lines in vitro. In vivo, tumor growth was more aggressive in the absence of host-derived SPARC resulting in decreased survival compared with WT mice (P = .005). Cisplatin did not improve survival of WT mice. In contrast, cisplatin therapy resulted in a significant survival advantage (P = .0048) and decreased tumor volume (P = .02) in SP-/- animals.
We conclude that SPARC is an important extracellular matrix protein that regulates the growth and chemosensitivity of ovarian cancer. In general, SPARC appears to control tumor cell growth but also impede the efficacy of cisplatin therapy. Therefore, selective inhibition of SPARC may provide an attractive strategy for increasing the efficacy of therapy in platinum-resistant ovarian tumors.

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Available from: Shanna A Arnold
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    • "As a result, it has been regarded as a therapeutic target for pancreatic adenocarcinoma [20] and gastric cancer [21] on the one hand, but as a therapeutic agent for colorectal [22,23] and ovarian [24] cancers on the other. Indeed, in ovarian cancer, SPARC has been shown to sensitize tumor cells to cisplatin therapy [24] and to enhance apoptosis and potentiate sensitivity to the chemotherapeutic agent 5-fluorouracil in colorectal cancer [23]. In the latter, this sensitivity was mediated by SPARC binding to procaspase 8. "
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    ABSTRACT: The current treatment regimen for glioma patients is surgery, followed by radiation therapy plus temozolomide (TMZ), followed by 6 months of adjuvant TMZ. Despite this aggressive treatment regimen, the overall survival of all surgically treated GBM patients remains dismal, and additional or different therapies are required. Depending on the cancer type, SPARC has been proposed both as a therapeutic target and as a therapeutic agent. In glioma, SPARC promotes invasion via upregulation of the p38 MAPK/MAPKAPK2/HSP27 signaling pathway, and promotes tumor cell survival by upregulating pAKT. As HSP27 and AKT interact to regulate the activity of each other, we determined whether inhibition of HSP27 was better than targeting SPARC as a therapeutic approach to inhibit both SPARC-induced glioma cell invasion and survival. Our studies found the following. 1) SPARC increases the expression of tumor cell pro-survival and pro-death protein signaling in balance, and, as a net result, tumor cell survival remains unchanged. 2) Suppressing SPARC increases tumor cell survival, indicating it is not a good therapeutic target. 3) Suppressing HSP27 decreases tumor cell survival in all gliomas, but is more effective in SPARC-expressing tumor cells due to the removal of HSP27 inhibition of SPARC-induced pro-apoptotic signaling. 4) Suppressing total AKT1/2 paradoxically enhanced tumor cell survival, indicating that AKT1 or 2 are poor therapeutic targets. 5) However, inhibiting pAKT suppresses tumor cell survival. 6) Inhibiting both HSP27 and pAKT synergistically decreases tumor cell survival. 7) There appears to be a complex feedback system between SPARC, HSP27, and AKT. 8) This interaction is likely influenced by PTEN status. With respect to chemosensitization, we found the following. 1) SPARC enhances pro-apoptotic signaling in cells exposed to TMZ. 2) Despite this enhanced signaling, SPARC protects cells against TMZ. 3) This protection can be reduced by inhibiting pAKT. 4) Combined inhibition of HSP27 and pAKT is more effective than TMZ treatment alone. We conclude that inhibition of HSP27 alone, or in combination with pAKT inhibitor IV, may be an effective therapeutic approach to inhibit SPARC-induced glioma cell invasion and survival in SPARC-positive/PTEN-wildtype and SPARC-positive/PTEN-null tumors, respectively.
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