Inverse regulation of melanoma growth and migration by Orai1/STIM2‐dependent calcium entry

Abstract

Spontaneous melanoma phenotype switching is controlled by unknown environmental factors and may determine melanoma outcome and responsiveness to anticancer therapy. We show that Orai1 and STIM2 are highly expressed and control store-operated Ca(2+) entry in human melanoma. Lower extracellular Ca(2+) or silencing of Orai1/STIM2 caused a decrease in intracellular Ca(2+) , which correlated with enhanced proliferation and increased expression of microphthalmia-associated transcription factor, a marker for proliferative melanoma phenotype. In contrast, the invasive and migratory potential of melanoma cells was reduced upon silencing of Orai1 and/or STIM2. Accordingly, markers for a non-proliferative, tumor-maintaining phenotype such as JARID1B and Brn2 decreased. Immunohistochemical staining of primary melanomas and lymph node metastases revealed a heterogeneous distribution of Orai1 and STIM2 with elevated expression in the invasive rim of the tumor. In summary, our results support a dynamic model in which Orai1 and STIM2 inversely control melanoma growth and invasion. Pharmacological tuning of Orai1 and particularly STIM2 might thus prevent metastatic spread and render melanomas more susceptible to conventional therapy.

STIM and Orai proteins as novel targets for cancer therapy. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis

“…Indeed, over 60% of skin cancer-related deaths are outcomes of metastatic melanomas (46) (97). Intriguingly, combined knockdown of STIM1 and STIM2 further abrogated SOCE, suggesting the possibility of a small but significant role of STIM1 in activating Orai1-mediated SOCE (97). Surprisingly, silencing of Orai1 and STIM2 in melanoma cells increased their proliferation but at the same time reduced their migratory and invasive capabilities (97).…”

“…If early diagnosis of melanoma is not achieved, it leads to metastasis. Indeed, over 60% of skin cancer-related deaths are outcomes of metastatic melanomas (46) (97). Intriguingly, combined knockdown of STIM1 and STIM2 further abrogated SOCE, suggesting the possibility of a small but significant role of STIM1 in activating Orai1-mediated SOCE (97).…”

STIM and ORAI proteins: crucial roles in hallmarks of cancer

“…In particular as reported above, Staniz et al (94) propose that STIM2-ORAI1-mediated SOCE expression switches the phenotype of melanocytes from proliferative to migratory. The data therefore show that STIM2 can act both as a tumor suppressor in highly proliferative cells (by increasing basal Ca 2ϩ to a level where it inhibits proliferation) as well as a tumor promoter in invasive cancers where the increased basal [Ca 2ϩ ] i results in a more invasive phenotype (94).…”

“…In particular, STIM2 has been proposed as an antiproliferative protein both in melanomas as well as in colorectal tumors (7,93,94). Interestingly, in humans, STIM2 is located at the short arm of chromosome 4, in 4p15.2, where loss of heterozygosis at 4p15 of the D4S2397 microsatellite marker has been previously associated with diminished disease-free survival and a more aggressive phenotype (5,7).…”

“…Interestingly, in humans, STIM2 is located at the short arm of chromosome 4, in 4p15.2, where loss of heterozygosis at 4p15 of the D4S2397 microsatellite marker has been previously associated with diminished disease-free survival and a more aggressive phenotype (5,7). In melanoma cells an intriguing role has been described for STIM2-ORAI1 expression in the switch from a more proliferative to a more migratory phenotype and vice versa (94 (94).…”