Abstract
Transient receptor potential melastatin subfamily member 7 (TRPM7) was essential in the growth and metastatic ability of prostate cancer cells. However, the effects and the relevant molecular mechanisms of TRPM7 on metastasis of prostate cancer under hypoxic atmosphere remain unclear. This study investigated the role of TRPM7 in the metastatic ability of androgen-independent prostate cancer cells under hypoxia. First, data mining was carried out to disclose the relationship between the TRPM7 gene level and the survival of prostate cancer patients. Specific siRNAs were used to knockdown target genes. Western blotting and qPCR were employed to determine protein and gene expression, respectively. The gene transcription activity was evaluated by luciferase activity assay of promoter gene. The protein interaction was determined by coimmunoprecipitation. Wound healing and transwell assays were employed to evaluated cell migration and invasion, respectively. Open access database results showed that high expression of TRPM7 was closely related to the poor survival of prostate cancer patients. Hypoxia simultaneously increased TRPM7 expression and induced HIF-1α accumulation in androgen-independent prostate cancer cells. Knockdown of TRPM7 significantly promoted HIF-1α degradation through the proteasome and inhibited EMT changes in androgen-independent prostate cancer cells under hypoxic condition. Moreover, TRPM7 knockdown increased the phosphorylation of RACK1 and strengthened the interaction between RACK1 and HIF-1α but attenuated the binding of HSP90 to HIF-1α. Whereas knockdown of RACK1 increased the binding of HSP90 to HIF-1α. Furthermore, both TRPM7 and HIF-1α knockdown significantly suppressed hypoxia-induced Annexin A1 protein expression, and suppression of HIF-1α/Annexin A1 signaling significantly inhibited hypoxia-induced cell migration and invasion of androgen-independent prostate cancer cells. Our findings demonstrate that TRPM7 knockdown promotes HIF-1α degradation via an oxygen-independent mechanism involving increased binding of RAKC1 to HIF-1α, and TRPM7-HIF-1α-Annexin A1 signaling axis plays a crucial role in the EMT, cell migration, and invasion of androgen-independent prostate cancer cells under hypoxic conditions.
Highlights
Hypoxic environments result from the rapid proliferation of cancer cells leading to insufficient blood supply, which is predominant in prostate cancer
This study demonstrated that hypoxia increased Transient receptor potential melastatin subfamily member 7 (TRPM7) expression and simultaneously induced Hypoxia-inducible factor 1α (HIF-1α) accumulation as well as epithelialmesenchymal transition (EMT) in androgen-independent prostate cancer cells
Knockdown of RACK1 resulted in increased binding of Heat Shock Protein 90 (HSP90) to HIF-1α to stabilize HIF-1α protein
Summary
Hypoxic environments result from the rapid proliferation of cancer cells leading to insufficient blood supply, which is predominant in prostate cancer. Hypoxia is a typical characteristic of prostate cancer and is a major pathological factor attributing to castration resistance and the metastasis of prostate cancer [1]. When suffering the hypoxic environments, prostate cancer cells regulate a series of gene expression and the corresponding pathways that were essential for cell survival and stress adaptation [2]. Previous researches reported that hypoxia strongly attributed to the poor prognosis and malignancy of prostate cancer [3, 4]. Targeting hypoxia relevant signaling pathways is essential in drug development and would be beneficial for the treatment of prostate cancer. Hypoxia-inducible factor 1α (HIF-1α) serving as one of the principal transcription factors is increased by hypoxia and accounts for the regulation of the expression of hypoxia-
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