The role of melanogenesis in regulation of melanoma behavior: Melanogenesis leads to stimulation of HIF-1α expression and HIF-dependent attendant pathways

Abstract

To study the effect of melanogenesis on HIF-1α expression and attendant pathways, we used stable human and hamster melanoma cell lines in which the amelanotic vs melanotic phenotypes are dependent upon the concentration of melanogenesis precursors in the culture media. The induction of melanin pigmentation led to significant up-regulation of HIF-1α, but not HIF-2α, protein in melanized cells for both lines. Similar upregulation of nuclear HIF-1α was observed in excisions of advanced melanotic vs. amelanotic melanomas. In cultured cells, melanogenesis also significantly stimulated expression of classical HIF-1-dependent target genes involved in angiogenesis and cellular metabolism, including glucose metabolism and stimulation of activity of key enzymes in the glycolytic pathway. Several other stress related genes containing putative HRE consensus sites were also upregulated by melanogenesis, concurrently with modulation of expression of HIF-1-independent genes encoding for steroidogenic emzymes, cytokines and growth factors. Immunohistochemical studies using a large panel of pigmented lesions revealed that higher levels of HIF-1α and GLUT-1 were detected in advanced melanomas in comparison to melanocytic nevi or thin melanomas localized to the skin. However, the effects on overall or disease free survival in melanoma patients were modest or absent for GLUT-1 or for HIF-1α, respectively. In conclusion, induction of the melanogenic pathway leads to robust upregulation of HIF-1-dependent and independent pathways in cultured melanoma cells, suggesting a key role for melanogenesis in regulation of cellular metabolism.

MicroRNA-138 suppresses proliferation, invasion and glycolysis in malignant melanoma cells by targeting HIF-1α

“…HIF-1α was observed to be upregulated in advanced MM compared with melanocytic nevi or thin melanomas localized to the skin (17). However, the regulatory mechanism of HIF-1α expression in MM has yet to be elucidated.…”

Evaluation of Anti-Melanogenic and Cytotoxic Activities of Phlomis caucasica on Human Melanoma SKMEL-3 Cells

“…Many published studies confirmed that melanin can increase the resistant of melanotic melanomas to chemo-, radio-and phototherapy. Therefore, anti-tyrosinase and antioxidant compounds have been able to prevent cellular mutations and tumor cells growth and increase therapeutic effectiveness of anti-melanoma drug through melanogenesis inhibition (3,4).…”

“…ROS can cause extensive cellular damage and decrease enzymatic antioxidant defense. Based on these observations, melanogenesis is involved in several human skin disorders, including pigmentation disorders and melanoma (3)(4)(5). Therefore, suppressing melanogenesis through inhibition tyrosinase activity together with increasing antioxidant status can be an effective strategy to achieve both anti-melanogenic and antimelanoma properties.…”

“…Afterwards, tyrosinase over activity increases some toxic and mutagenic intermediates of melanogenesis as well as hyperpigmentation. Moreover, it can affect the melanoma cells' behavior through autophagy effect on tumor cells (1)(2)(3). The melanin can protect malignant melanocytes as well as normal melanocytes from numerous physical and chemical damages.…”

Bioactivities in the tamarind seed extracts: A preliminary study

“…Melanin has been established as a protective factor against ultraviolet radiations. Disparity in the synthesis of melanin has also been associated with pre-cancerous, benign and patchy skin lesions, such as, vitiligo, lentigo, ephelis, naevi, macules and melanoma (7,8,9). Melanin related intracellular stress is associated with an increased expression of certain mitochondrial heat shock proteins such as mortalin, HSP60 and HSP70 (6).…”