IGIB researchers have for the first time identified a calcium sensor protein (STIM1) that independently regulates both skin cancer and pigmentation. Since different parts of the STIM1 protein activate two independent signalling pathways that control melanoma growth and pigmentation, drug can be developed to target specific sites in the STIM1 protein to control tumour growth or regulate pigmentation.
Researchers at Delhi’s CSIR-Institute of Genomics and Integrative Biology (IGIB) have for the first time identified a calcium sensor protein (STIM1) that independently regulates both skin cancer and pigmentation. The STIM1 protein does so by activating two independent signalling pathways.
Interestingly, different parts of the STIM1 protein activate the two independent signalling pathways that control melanoma growth and pigmentation. This opens up the possibility of developing drug molecules that target specific sites in the STIM1 protein to control tumour growth or regulate pigmentation.
While skin cancers account for third highest number of cancer associated deaths worldwide, perturbations in pigmentation pathways result in pigmentation disorders such as solar lentigo, melasma, vitiligo, and pityriasis alba. Current therapeutic regimes are not efficient in alleviating pigmentation disorders.
Role of STIM1 in melanoma
“The role of STIM1 in breast cancer and prostrate cancer is already known. Based on this, we hypothesised that STIM1 might have a role in melanoma growth as well,” says Dr. Rajender K Motiani from the Systems Biology Group at IGIB who led the team of researchers.
To study the role of STIM1 protein in melanoma growth in vitro, the researchers used STIM1 knockdown mouse cells and injected them into mouse models and observed the growth of melanoma. Compared with controls, melanoma growth was reduced by as much as 75% in mice that were injected with STIM1 knockdown cells.
While trying to find novel players that could potentially regulate pigmentation, the researchers identified a few signalling pathways which were differently regulated with change in pigmentation level.
When chemicals were used to change the levels of pigmentation of melanocytes, the researchers found that along with changes in melanin levels, other signalling modules were also changing. Similarly, melanin level reduced when pigmentation decreased. A surprising finding was that when pigmentation was decreasing, the calcium signalling pathway was also decreasing. “We got a hint that the STIM1 protein, which is a key regulator of calcium signalling pathway, would be regulating pigmentation too,” says Jyoti Tanwar from IGIB and one of the authors of the paper published in The EMBO Journal.
To confirm the role of STIM1 protein in pigmentation, the researchers knocked down the protein in melanocytes. This resulted in a reduction in pigmentation levels. “We further validated the role of STIM1 in regulating pigmentation in zebrafish models,” Dr. Motiani says. “The knockdown of STIM1 significantly decreased pigmentation in zebrafish embryos. Both in vitro and zebrafish studies established the critical role of STIM1 protein in pigmentation.”
The protein mediates calcium entry into cells and this leads to melanoma growth. “So calcium entry into cells can be an attractive chemotherapy target for melanoma,” says Dr. Motiani.
“We will next be studying biopsy samples of human pigmentary disorders. Our research has led to identification of a novel molecular target with high translational value,” says Tanwar.