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Progesterone induces cell apoptosis via the CACNA2D3/Ca2+/p38 MAPK pathway in endometrial cancer

Xiangnan Kong¹, Min Li², Kai Shao¹

¹Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.

Oncology Reports

|November 21, 2019

Abstract:

Endometrial cancer (EC) is one of the most common malignant gynecological tumors in women. The main treatments for EC (surgery, chemotherapy and radiation therapy) produce significant side effects. Thus, it is urgent to identify promising therapeutic targets and prognostic markers. CACNA2D3, as a member of the calcium channel regulatory α2δ subunit family, is reported to exert a tumor suppressive effect in numerous cancers. However, the function of CACNA2D3 in EC is not well known. In the present study, CACNA2D3 was lowly expressed in EC tissues and cells. The overexpression of CACNA2D3 via lentiviral particle injection significantly blocked the tumor growth in an in vivo xenograft model. In vitro, the overexpression of CACNA2D3 markedly inhibited cell proliferation and migration, and promoted cell apoptosis and calcium influx. These data revealed that CACNA2D3 functions as a tumor suppressor in EC. It was also revealed that the addition of progesterone (P4) blocked tumor growth in Ishikawa‑injected nude mice. P4 induced the expression of CACNA2D3 in vivo and in vitro, and the silencing of CACNA2D3 affected P4‑inhibited cell proliferation and P4‑induced cell apoptosis and calcium influx. In Ishikawa cells, P4 enhanced the expression of phosphorylated (p)‑p38 MAPK and PTEN, but blocked the levels of p‑PI3K and p‑AKT. The knockdown of CACNA2D3 blocked the function of P4. These data revealed that P4 promoted cell apoptosis via the activation of the CACNA2D3/Ca2+/p38 MAPK pathway, and blocked cell proliferation via suppression of the PI3K/AKT pathway. Collectively, these findings indicated the antitumor role of CACNA2D3 in EC, and revealed the mechanism of P4 inhibition of EC progression, which provided a new target for EC therapy and new evidence for P4 in EC therapy.

Insights

Calcium channel subunit CACNA2D3 acts as a tumor suppressor in endometrial cancer (EC). Progesterone (P4) enhances CACNA2D3 expression, inhibiting EC cell proliferation and promoting apoptosis via specific molecular pathways.

Area of Science:

Gynecology
Oncology
Molecular Biology
Calcium Channel Biology

Background:

Endometrial cancer (EC) is a common gynecological malignancy with significant treatment side effects.
There is an urgent need for novel therapeutic targets and prognostic markers for EC.
CACNA2D3, a calcium channel subunit, shows tumor-suppressive roles in various cancers, but its function in EC is largely unknown.

Purpose of the Study:

To investigate the role of CACNA2D3 in endometrial cancer.
To elucidate the underlying molecular mechanisms of CACNA2D3's function in EC.
To explore the potential therapeutic implications of CACNA2D3 and progesterone (P4) in EC treatment.

Main Methods:

Quantitative analysis of CACNA2D3 expression in EC tissues and cells.
In vivo xenograft models to assess tumor growth inhibition by CACNA2D3 overexpression.
In vitro assays to evaluate the effects of CACNA2D3 on cell proliferation, migration, and apoptosis.
Investigation of progesterone's effects on EC cells and tumor growth, including its interaction with CACNA2D3.
Western blot analysis to examine signaling pathways (p38 MAPK, PTEN, PI3K/AKT) involved in P4 and CACNA2D3 actions.

Main Results:

CACNA2D3 was found to be lowly expressed in EC tissues and cells.
Overexpression of CACNA2D3 significantly inhibited tumor growth in vivo and suppressed proliferation and migration while promoting apoptosis and calcium influx in vitro.
Progesterone (P4) administration blocked tumor growth, induced CACNA2D3 expression, and its effects on proliferation, apoptosis, and calcium influx were dependent on CACNA2D3.
P4 modulated the p38 MAPK and PI3K/AKT pathways, with CACNA2D3 knockdown interfering with these P4-mediated effects.

Conclusions:

CACNA2D3 functions as a tumor suppressor in endometrial cancer.
Progesterone inhibits EC progression by activating the CACNA2D3/Ca2+/p38 MAPK pathway and suppressing the PI3K/AKT pathway.
CACNA2D3 represents a potential therapeutic target, and progesterone shows promise for EC therapy.

Read full analysis

Keywords:

endometrial cancer CACNA2D3 progesterone cell apoptosis mitogen-activated protein kinase pathway

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