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Published on: December 31, 2013
TRPV6 determines the effect of vitamin D3 on prostate cancer cell growth
V'yacheslav Lehen'kyi1, Maylis Raphaël, Agathe Oulidi
1Inserm, U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, France.
Abstract:
Despite remarkable advances in the therapy and prevention of prostate cancer it is still the second cause of death from cancer in industrialized countries. Many therapies initially shown to be beneficial for the patients were abandoned due to the high drug resistance and the evolution rate of the tumors. One of the prospective therapeutical agents even used in the first stage clinical trials, 1,25-dihydroxyvitamin D3, was shown to be either unpredictable or inefficient in many cases. We have already shown that TRPV6 calcium channel, which is the direct target of 1,25-dihydroxyvitamin D3 receptor, positively controls prostate cancer proliferation and apoptosis resistance (Lehen'kyi et al., Oncogene, 2007). However, how the known 1,25-dihydroxyvitamin D3 antiproliferative effects may be compatible with the upregulation of pro-oncogenic TRPV6 channel remains a mystery. Here we demonstrate that in low steroid conditions 1,25-dihydroxyvitamin D3 upregulates the expression of TRPV6, enhances the proliferation by increasing the number of cells entering into S-phase. We show that these pro-proliferative effects of 1,25-dihydroxyvitamin D3 are directly mediated via the overexpression of TRPV6 channel which increases calcium uptake into LNCaP cells. The apoptosis resistance of androgen-dependent LNCaP cells conferred by TRPV6 channel is drastically inversed when 1,25-dihydroxyvitamin D3 effects were combined with the successful TRPV6 knockdown. In addition, the use of androgen-deficient DU-145 and androgen-insensitive LNCaP C4-2 cell lines allowed to suggest that the ability of 1,25-dihydroxyvitamin D3 to induce the expression of TRPV6 channel is a crucial determinant of the success or failure of 1,25-dihydroxyvitamin D3-based therapies.
Insights
1,25-dihydroxyvitamin D3 can unexpectedly promote prostate cancer growth by upregulating TRPV6 calcium channels, especially in low-steroid conditions. Targeting TRPV6 may improve vitamin D therapies for prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Calcium Channel Research
Background:
- Prostate cancer remains a leading cause of cancer death despite therapeutic advances.
- High drug resistance and tumor evolution limit treatment efficacy.
- 1,25-dihydroxyvitamin D3, a potential therapeutic, shows unpredictable outcomes in prostate cancer.
- TRPV6 calcium channel, a target of vitamin D, promotes prostate cancer proliferation and apoptosis resistance.
Purpose of the Study:
- To elucidate the mechanism behind 1,25-dihydroxyvitamin D3's paradoxical effects on prostate cancer.
- To investigate the role of TRPV6 channel in mediating vitamin D's pro-proliferative and anti-apoptotic effects.
- To determine if TRPV6 expression influences the efficacy of vitamin D-based prostate cancer therapies.
Main Methods:
- Investigated 1,25-dihydroxyvitamin D3 effects on TRPV6 expression in prostate cancer cell lines (LNCaP, DU-145, LNCaP C4-2) under varying steroid conditions.
- Utilized TRPV6 knockdown to assess its role in mediating vitamin D's effects.
- Measured cell proliferation (S-phase entry) and apoptosis resistance.
- Analyzed calcium influx via TRPV6 channels.
Main Results:
- In low steroid conditions, 1,25-dihydroxyvitamin D3 upregulates TRPV6 expression and enhances prostate cancer cell proliferation by increasing S-phase entry.
- Overexpression of TRPV6 mediates these pro-proliferative effects through increased calcium uptake.
- TRPV6 knockdown reverses the apoptosis resistance conferred by TRPV6 in androgen-dependent cells treated with vitamin D.
- The ability of 1,25-dihydroxyvitamin D3 to induce TRPV6 expression correlates with therapeutic success in different prostate cancer models.
Conclusions:
- 1,25-dihydroxyvitamin D3 can paradoxically promote prostate cancer proliferation and apoptosis resistance by upregulating TRPV6, particularly in low-steroid environments.
- TRPV6 channel activity is a critical mediator of these effects, influencing calcium homeostasis and cell cycle progression.
- TRPV6 expression levels are a key determinant of 1,25-dihydroxyvitamin D3 efficacy in prostate cancer treatment, suggesting it as a potential therapeutic target or biomarker.
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