Inhibition of Transient Receptor Potential Vanilloid 6 channel, elevated in human ovarian cancers, reduces tumour growth in a xenograft model

Abstract

Background: Transient Receptor Potential Vanilloid 6 (TRPV6), a non-voltage gated calcium channel, is implicated in malignancies and correlates with Gleason scores in prostate cancer and with poor prognosis in breast cancer. Data on the TRPV6 status of ovarian malignancies has not received significant attention. The effect of inhibiting TRPV6 activity on ovarian tumour growth has never been reported.Methods: We quantified TRPV6 mRNA and protein in biopsies of five types of ovarian cancer at different stages and grades by quantitative PCR and immunohistochemistry respectively. We verified the presence of TRPV6 in SKOV-3 cells and xenografts by Western Blotting. NOD/SCID mice bearing xenografted ovarian tumours derived from SKOV-3 were treated daily with TRPV6-antagonistic peptides (SOR-C13 and SOR-C27) at 400, 600 and 800 mg/kg delivered intraperitoneally (i.p.) over 12 days. Data from qPCR and tumour growth experiments were compared with a Student's t-test. Immunohistochemical ranking of staining were compared with Kruskall-Wallace one-way ANOVA and Dunn's Multiple Comparison post-test.Results: TRPV6 mRNA and protein are significantly elevated at all stages and grades of 5 ovarian cancer types over normal tissue. Overall qPCR log2 values (n, mean, ± SEM) for mRNA in tumour (n = 165, 5.06 ± 0.16) were greater (p < 0.05) than normal tissues (n = 26, 0.45 ± 0.41). All stages and grades included in the biopsy arrays were significantly greater than normal tissues. Immunohistochemical staining of TRPV6 was ranked >2 (faint in most cells) in 80.5% of tumours (123) while 92% of normal tissues (23) ranked ≤ 2. Daily i.p. injection with SOR-C13 (400, 600 and 800 mg/kg) over 12 days inhibits tumour growth (59%) at the highest dose compared to non-treated controls. SOR-C27 at 800 mg/kg SOR-C27 inhibited tumour growth 55% after 12 days. Results of daily and intermittent dosing (Days 1, 2, 3 and 8, 9, 10) with SOR-C13 were indistinguishable.Conclusion: TRPV6 mRNA and protein are elevated in biopsies of ovarian cancers compared to normal tissue. Inhibition of TRPV6 activity significantly reduces ovarian tumour growth providing evidence that TRPV6 is a feasible oncology target in ovarian cancers.

TRPV6 calcium channel directs homeostasis of the mammary epithelial sheets and controls epithelial mesenchymal transition

“…A number of TRPV6 inhibitors have already shown potential in reducing cell growth f.i. in breast cancer models [63][64][65][66][67] . Whether these same inhibitors also impact EMT, needs to be studied.…”

Targeting the Calcium Signalling Machinery in Cancer

“…Interestingly, in human small cell lung carcinoma cells, the classical TRPV1 agonist capsaicin induces apoptosis via TRPV6, independent of TRPV1, in a Ca 2+ - and calpain-dependent manner [ 192 ]. These advances have led to preclinical and clinical studies assessing TRPV6 as a therapeutic target; the selective TRPV6 inhibitor SOR-C13 has shown promise in both in vivo models of cancer [ 193 ] and early clinical trials in patients with advanced tumours of epithelial origin [ 194 ].…”

TRPV6 as A Target for Cancer Therapy

“…Ovarian cancer was cited in an early study as over-producing TRPV6 protein in one biopsy 40, but only recently was a survey of the five different types of ovarian cancer (low grade serous, high grade serous, clear cell, endometrioid, mucinous) reported 100. As always, care should be taken in assessing reported amounts of TRPV6 protein since there is often difficulty with available antibodies.…”