EP4 and Class III β-Tubulin Expression in Uterine Smooth Muscle Tumors: Implications for Prognosis and Treatment

Abstract

The microtubule-stabilizing agent docetaxel in combination with gemcitabine represents one of the most effective regimens against the aggressive gynecologic tumor leiomyosarcoma (LMS). Upregulation of class III β-tubulin has previously been shown to confer taxane resistance in a variety of human cancers. Prostaglandin E2 receptor EP4 is linked to progression of a variety of human cancers and may represent a novel target for tumor inhibition in LMS. We evaluated the hypotheses that EP4 and class III β-tubulin have increased expression in LMS in comparison to normal myometrium or benign tumors and that expression of class III β-tubulin correlates with resistance to taxanes and poor clinical outcome. Gene expression was examined using TCGA data and correlated with clinicopathologic outcome which demonstrated that class III β-tubulin is more highly expressed in more aggressive sarcomas with EP4 being widely expressed in all subtypes of sarcoma. Immunohistochemistry for EP4 and class III β-tubulin was performed on patients with LMS, leiomyomatosis/STUMP, leiomyoma, and normal myometrium. Expression of EP4 and class III β-tubulin were characterized for cell lines SK-UT-1, SK-UT-1B, and PHM-41 and these cell lines were treated with docetaxel alone and in combination with EP4 inhibitors. In taxane-resistant cell lines that overexpress class III β-tubulin and EP4, treatment with EP4 inhibitor resulted in at least 2-fold sensitization to docetaxel. Expression of class III β-tubulin and EP4 in LMS may identify patients at risk of resistance to standard chemotherapies and candidates for augmentation of therapy through EP4 inhibition.

Eicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapy

“…There is growing interest in the potential of EP4 antagonists in combination with other therapies, including chemotherapy. Gynecologic uterine smooth muscle tumors are sensitized to docetaxel in the presence of the EP4 antagonists AH23848 or RQ15986 (Reader et al, 2019). In a model of oxaliplatin-resistant colon cancer, EP4 blockade with L161982 inhibited CSC markers and tumorsphere formation (Huang et al, 2019).…”

Intrinsic and Extrinsic Factors Affecting Microtubule Dynamics in Normal and Cancer Cells

“…In a wide range of tumors and cancer cell lines, including small-cell lung carcinoma, NSCLC, ovarian, prostate, bladder, uterine, upper gastrointestinal, colon, pancreatic, LASCCHN, and gastric cancer, βIII upregulation is associated with the development of resistance to taxane-based chemotherapy and poor clinical outcome [ 121 , 200 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 210 , 211 , 212 , 213 , 215 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 ]. Moreover, an increased βIII level was also shown to be associated with EMT and cell motility of colon cancer cell lines [ 234 ].…”

The Role of Eicosanoids in Gynecological Malignancies

“…COX-2 expression was higher in uterine fibroids compared to healthy smooth muscle cells and selective COX-2 inhibitor celecoxib decreased fibroid cell proliferation and PGE 2 secretion (Ke et al, 2013). Recently, in a study published by Reader et al (2019), the role of EP4 was evaluated in LMS proliferation and migration. While minimal effects in proliferation was observed with monotherapy treatment of LMS with an EP4 inhibitor when combined with docetaxel treatment, we saw a sensitization of LMS cells to chemotherapeutic treatment (Reader et al, 2019).…”

“…Recently, in a study published by Reader et al (2019), the role of EP4 was evaluated in LMS proliferation and migration. While minimal effects in proliferation was observed with monotherapy treatment of LMS with an EP4 inhibitor when combined with docetaxel treatment, we saw a sensitization of LMS cells to chemotherapeutic treatment (Reader et al, 2019). In addition to sensitization to chemotherapy, we also demonstrated a significant decrease in LMS cell migration.…”