Activation of the tumor suppressive Hippo pathway by triptonide as a new strategy to potently inhibit aggressive melanoma cell metastasis.

Metastatic melanoma has a very high mortality rate despite the availability of chemotherapy, radiotherapy, and immunotherapy; therefore, more effective therapeutics are needed. The Hippo pathway plays an inhibitory role in melanoma progression, but the tumor suppressors Salvador homolog-1 (SAV1) and large tumor suppressor 1 (LATS1) in this pathway are down-regulated in melanoma. As a result, the downstream oncogenic Yes-associated protein (YAP) is active, resulting in uncontrolled melanoma growth and metastasis. Therapeutics for remedying SAV1 and LATS1 deficiency in melanoma have not yet been reported in the literature. Here, we show that the small molecule triptonide (MW 358 Da) robustly suppressed melanoma cell tumorigenicity, migration, and invasion. Furthermore, triptonide markedly reduced tumor growth and melanoma lung metastasis in tumor-bearing mice with low toxicity. Molecular mechanistic studies revealed that triptonide promoted SAV1 and LATS1 expression, strongly activated the tumor-suppressive Hippo pathway, degraded oncogenic YAP via the lysosomal pathway, and reduced levels of tumorigenic microphthalmia-associated transcription factor (MITF) in melanoma cells. Triptonide also strongly inhibited activation of AKT, a SAV1-binding signaling protein. Collectively, our results conceptually demonstrate that induction of SAV1 and LATS1 expression and activation of the tumor-suppressive Hippo pathway by triptonide potently inhibits aggressive melanoma cell growth and metastasis. These findings suggest a new strategy for developing therapeutics to treat metastatic melanoma and highlight a novel drug candidate against aggressive melanoma.