Suppression of TRPM7 Inhibited Hypoxia-Induced Migration and Invasion of Androgen-Independent Prostate Cancer Cells by Enhancing RACK1-Mediated Degradation of HIF-1α

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.

O-GlcNAcylation homeostasis controlled by calcium influx channels regulates multiple myeloma dissemination

“…Genetic downregulation of TRPM7 was shown to inhibit hypoxia-induced cell motility in androgen-independent prostate cancer cells. Such inhibition was mediated through proteasomal degradation of HIF-1α, which resulted in stabilization and increased binding of HIF-1α to RACK1, [ 47 ] suggesting the role of Ca 2+ influx in protein stability and function. In the present study, we demonstrated for the first time the role of Ca 2+ influx through TRPM7, STIM1 and ORAI1 channels in controlling protein stability and function via O -GlcNAcylation.…”

Construction of Potential Gene Expression and Regulation Networks in Prostate Cancer Using Bioinformatics Tools

“…Therefore, the loss of ANXA1 may be a useful marker for the development and progression of prostate cancer. However, some studies have proven that the expression of ANXA1 is negatively Oxidative Medicine and Cellular Longevity correlated with androgen receptor (AR), and the expression of ANXA1 increases after AR knockdown or AR antagonists are used, which accelerates the invasion and metastasis of advanced PCa [25,26]. ANXA1 may act as a tumor inhibitor in the early stage of cancer, but in the late stage of cancer, it may play the opposite role.…”

Alteration and dysfunction of ion channels/transporters in a hypoxic microenvironment results in the development and progression of gastric cancer

“…Recent studies have shown that hypoxia can simultaneously increase transient receptor almelastatin-like7 channel (TRPM7) expression and induce HIF-1α accumulation in androgen-independent prostate cancer cells. TRPM7 silencing, however, significantly promoted hypoxia-inducible factor 1 alpha (HIF-1α) degradation through the proteasome and inhibited EMT changes in androgen-independent prostate cancer cells under hypoxic conditions [23]. Numerous studies have shown that HIF-1α acts as a main transcription factor that mediates hypoxic responses and promotes the transcription of angiogenic factors such as VEGF, which leads to an increase in glycolysis through the inhibition of mitochondrial oxidative phosphorylation [24].…”