Tubeimoside I Inhibits Cell Proliferation and Induces a Partly Disrupted and Cytoprotective Autophagy Through Rapidly Hyperactivation of MEK1/2-ERK1/2 Cascade via Promoting PTP1B in Melanoma

Abstract

Tubeimoside I (TBMS1), also referred to as tubeimoside A, is a natural compound extracted from the plant Tu Bei Mu (<i>Bolbostemma paniculatum</i>), which is a traditional Chinese herb used to treat multiple diseases for more than 1,000 years. Studies in recent years reported its anti-tumor activity in several cancers. However, whether it is effective in melanoma remains unknown. In the current study, we discovered that TBMS1 treatment inhibited melanoma cell proliferation <i>in vitro</i> and tumorigenecity <i>in vivo</i>. Besides, we also observed that TBMS1 treatment induced a partly disrupted autophagy, which still remained a protective role, disruption of which by chloroquine (CQ) or 3-methyladenine (3-MA) enhanced TBMS1-induced cell proliferation inhibition. CQ combined with TBMS1 even induced cellular apoptosis. BRAF(V600E) mutation and its continuously activated downstream MEK1/2-ERK1/2 cascade are found in 50% of melanomas and are important for malanomagenesis. However, hyperactivating MEK1/2-ERK1/2 cascade can also inhibit tumor growth. Intriguingly, we observed that TBMS1 rapidly hyperactivated MEK1/2-ERK1/2, inhibition of which by its inhibitor SL-327 rescued the anti-cancerous effects of TBMS1. Besides, the targets of TBMS1 were predicted by the ZINC Database based on its structure. It is revealed that protein-tyrosine phosphatase 1B (PTP1B) might be one of the targets of TBMS1. Inhibition of PTP1B by its selective inhibitor TCS401 or shRNA rescued the anti-cancerous effects of TBMS1 in melanoma cells. These results indicated that TBMS1 might activate PTP1B, which further hyperactivates MEK1/2-ERK1/2 cascade, thereby inhibiting cell proliferation in melanoma. Our results provided the potentiality of TBMS1 as a drug candidate for melanoma therapy and confirmed that rapidly hyperactivating an oncogenic signaling pathway may also be a promising strategy for cancer treatment.