Resistance to ursolic acid-induced apoptosis through involvement of melanogenesis and COX-2/PGE2 pathways in human M4Beu melanoma cancer cells.

Melanoma is one of the most aggressive forms of cancer with a continuously growing incidence worldwide and is usually resistant to chemotherapy agents, which is due in part to a strong resistance to apoptosis. Previously, we had showed that B16-F0 murine melanoma cells undergoing apoptosis are able to delay their own death induced by ursolic acid (UA), a natural pentacyclic triterpenoid compound. We had demonstrated that tyrosinase and TRP-1 up-regulation in apoptotic cells and the subsequent production of melanin were implicated in an apoptosis resistance mechanism. Several resistance mechanisms to apoptosis have been characterized in melanoma such as hyperactivation of DNA repair mechanisms, drug efflux systems, and reinforcement of survival signals (PI3K/Akt, NF-κB and Raf/MAPK pathways). Otherwise, other mechanisms of apoptosis resistance involving different proteins, such as cyclooxygenase-2 (COX-2), have been described in many cancer types. By using a strategy of specific inhibition of each ways, we suggested that there was an interaction between melanogenesis and COX-2/PGE2 pathway. This was characterized by analyzing the COX-2 expression and activity, the expression of tyrosinase and melanin production. Furthermore, we showed that anti-proliferative and proapoptotic effects of UA were mediated through modulation of multiple signaling pathways including Akt and ERK-1/2 proteins. Our study not only uncovers underlying molecular mechanisms of UA action in human melanoma cancer cells but also suggest its great potential as an adjuvant in treatment and cancer prevention.

[1]  A. Enk,et al.  COX-2 expression in malignant melanoma: a novel prognostic marker? , 2009, Melanoma research.

[2]  A. Young,et al.  Melanogenesis: a photoprotective response to DNA damage? , 2005, Mutation research.

[3]  Michael R Hamblin,et al.  Melanoma resistance to photodynamic therapy: new insights , 2013, Biological chemistry.

[4]  V. Hearing,et al.  Enzymatic control of pigmentation in mammals , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[5]  D. Tobin,et al.  Prostaglandin-E2 is produced by adult human epidermal melanocytes in response to UVB in a melanogenesis-independent manner , 2010, Pigment cell & melanoma research.

[6]  A. Brożyna,et al.  Inhibition of melanogenesis as a radiation sensitizer for melanoma therapy , 2008, International journal of cancer.

[7]  D. Tobin,et al.  Melanin pigmentation in mammalian skin and its hormonal regulation. , 2004, Physiological reviews.

[8]  F. Sinicrope,et al.  Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cells. , 2002, Cancer research.

[9]  Z. Ronai,et al.  Death receptors and melanoma resistance to apoptosis , 2003, Oncogene.

[10]  M. Hansen,et al.  Overexpression of COX-2 in human osteosarcoma cells decreases proliferation and increases apoptosis. , 2006, Cancer research.

[11]  B. Liagre,et al.  The P2Y2/Src/p38/COX-2 pathway is involved in the resistance to ursolic acid-induced apoptosis in colorectal and prostate cancer cells. , 2012, Biochimie.

[12]  S. Katiyar,et al.  Berberine, an isoquinoline alkaloid, inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E₂ and prostaglandin E₂ receptors. , 2011, Carcinogenesis.

[13]  R. Duval,et al.  Differential involvement of mitochondria during ursolic acid-induced apoptotic process in HaCaT and M4Beu cells. , 2008, Oncology reports.

[14]  M. Fittall,et al.  Evaluating Biomarkers in Melanoma , 2015, Front. Oncol..

[15]  Randy Gordon,et al.  Skin cancer: an overview of epidemiology and risk factors. , 2013, Seminars in oncology nursing.

[16]  K. Chun,et al.  Cyclooxygenase-2 inhibits UVB-induced apoptosis in mouse skin by activating the prostaglandin E2 receptors, EP2 and EP4. , 2007, Cancer research.

[17]  L. Davids,et al.  Photodynamic therapy‐induced killing is enhanced in depigmented metastatic melanoma cells , 2011, Cell biology international.

[18]  C. Denkert,et al.  Expression of cyclooxygenase 2 in human malignant melanoma. , 2001, Cancer research.

[19]  Sung-Jan Lin,et al.  Cyclooxygenase-2 overexpression in human basal cell carcinoma cell line increases antiapoptosis, angiogenesis, and tumorigenesis. , 2006, The Journal of investigative dermatology.

[20]  Heather R. Roberts,et al.  The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. , 2009, Carcinogenesis.

[21]  Rajiv Kumar,et al.  Genetics of pigmentation in skin cancer--a review. , 2010, Mutation research.

[22]  N. Swanson,et al.  Arachidonic acid metabolites in cutaneous carcinomas. Evidence suggesting that elevated levels of prostaglandins in basal cell carcinomas are associated with an aggressive growth pattern. , 1986, Archives of dermatology.

[23]  J. Rundhaug,et al.  Cyclo‐oxygenase‐2 Plays a Critical Role in UV‐induced Skin Carcinogenesis † , 2008, Photochemistry and photobiology.

[24]  B. Liagre,et al.  Cyclopamine and jervine induce COX-2 overexpression in human erythroleukemia cells but only cyclopamine has a pro-apoptotic effect. , 2013, Experimental cell research.

[25]  S. Tawata,et al.  Mimosine Dipeptide Enantiomsers: Improved Inhibitors against Melanogenesis and Cyclooxygenase , 2015, Molecules.

[26]  B. Liagre,et al.  Low dose leflunomide activates PI3K/Akt signalling in erythroleukemia cells and reduces apoptosis induced by anticancer agents , 2006, Apoptosis.

[27]  B. Chwirot,et al.  Expression of cyclooxygenase-2 in benign naevi and during human cutaneous melanoma progression , 2006, Melanoma research.

[28]  M. Gottesman,et al.  Involvement of ABC transporters in melanogenesis and the development of multidrug resistance of melanoma , 2009, Pigment cell & melanoma research.

[29]  R. DuBois,et al.  PROSTAGLANDINS AND CANCER , 2005, Gut.

[30]  T. Kishida,et al.  Therapeutic RNA interference of malignant melanoma by electrotransfer of small interfering RNA targeting Mitf , 2007, Gene Therapy.

[31]  M. Montenegro,et al.  Melanoma coordinates general and cell-specific mechanisms to promote methotrexate resistance. , 2012, Experimental cell research.

[32]  B. Liagre,et al.  Cyclooxygenase-2 positively regulates Akt signalling and enhances survival of erythroleukemia cells exposed to anticancer agents , 2013, Apoptosis.

[33]  T. Hla,et al.  Cyclooxygenase‐2 modulates cellular growth and promotes tumorigenesis , 2003, Journal of cellular and molecular medicine.

[34]  J. Doré,et al.  Tumour-associated antigens in culture medium of malignant melanoma cell strains , 1979, Cancer Immunology, Immunotherapy.

[35]  S. Lowe,et al.  Apoptosis and melanoma chemoresistance , 2003, Oncogene.

[36]  B. Liagre,et al.  HT-29 colorectal cancer cells undergoing apoptosis overexpress COX-2 to delay ursolic acid-induced cell death. , 2011, Biochimie.

[37]  B. Liagre,et al.  A novel form of melanoma apoptosis resistance: melanogenesis up-regulation in apoptotic B16-F0 cells delays ursolic acid-triggered cell death. , 2011, Experimental cell research.

[38]  S. Y. Kim,et al.  The antimycotic agent clotrimazole inhibits melanogenesis by accelerating ERK and PI3K‐/Akt‐mediated tyrosinase degradation , 2015, Experimental dermatology.

[39]  R. Duval,et al.  Ursolic acid induces apoptosis through mitochondrial intrinsic pathway and caspase‐3 activation in M4Beu melanoma cells , 2005, International journal of cancer.

[40]  B. Chwirot,et al.  Cyclooxygenase-2 (COX-2): first immunohistochemical marker distinguishing early cutaneous melanomas from benign melanocytic skin tumours , 2007, Melanoma research.

[41]  Ji Young Kim,et al.  siRNA‐mediated knock‐down of COX‐2 in melanocytes suppresses melanogenesis , 2012, Experimental dermatology.