There is not magic cured for malignant melanoma (MM) [
1‐
3]. Surgery and chemotherapy are the routine therapies to suppress the MM progression. But these treatments cannot effectively control the recurrence and distant metastasis. There are several MM suppressive drugs or compounds which associated with autophagy induction. For example, roselle (
Hibiscus sabdariffa) leaf extract increased the expressions of autophagy-related proteins including autophagy-related gene 5 (ATG5), beclin1, light chain 3-II (LC3-II), and induced autophagic cell death in A375 cells [
19]. Curcumin (the yellow spice derived from the rhizome of
Curcuma longa) effectively inhibited the proliferation and invasion through autophagy induction in A375 and C8161 cells [
20]. Imiquimod increased autophagy and apoptosis to induce cell death in a dose and time dependent manner in basal cell carcinoma (BCC) cells [
21]. Tan II A has been shown to inhibit esophageal, colon, and other cancers proliferation through the induction of cell apoptosis and differentiation [
22,
23]. Tan II A induced intracellular generation of reactive oxygen species (ROS) to regulate autophagy and apoptosis in lung cancer cell [
11]. Tan II A activated AMPK, ERK and suppressed mTOR, p70S6 K to induce autophagy and apoptosis in leukemic KBM-5 cells [
12]. Light chain micro-protein 3 (LC3) is autophagy universal marker which included two subtypes LC3-I and LC3-II. LC3-I is a soluble cytoplasmic protein expressed in normal condition. When cell initiates autophagocytosis, LC3-I interacts with autophagic protein PE by ubiquitin-like modification process to transform to LC3-II membrane protein [
24]. LC3-II expression reflects to the mature stages of autophagy. LC3-II levels associate with autophagic bodies in cell and is a convention marker for autophagy activity [
24]. Beclin-1 plays an important role in promoting the formation of autophagic vesicles during the cell autophagocytosis process in melanoma [
8]. We therefore monitored both LC-II and beclin-1 protein expression to assess their association with autophagocytosis. In this report, we found that Tan II A inhibited melanoma A375 cells proliferation in a dose and time dependent manner. Higher concentration of Tan II A (from 4, 2, 1 to 0.5 μg/mL) and longer culture time (from 72, 48 h to 24 h) showed stronger inhibition on A375 cells proliferations compared to the negative control. Tan II A also significantly inhibited other melanoma MV3 and M14 cell and modestly reduced other human cell line including Hacat, HUVEC growth. We observed that Tan IIA reduced A375 cells invasion in a dose dependent manner. Tan II A also decreased the CXCL12-induced A375 cell migration [
25]. Moreover, TanII A promoted autophagic body production on A375 in a dose dependent manner. Tan II A up-regulated the autophagocytosis related genes including Beclin-1 and LC3-II protein expressions in a dose dependent manner. However, TanII A inhibited the phosphorylation of phosphatidylinositol 3-kinase (PI3K), phosphorylated (p) - protein kinase B (P-Akt), p- mammalian target of rapamycin (p-mTOR), and p-p70S6K1 in A375 cells. The PI3K- AKT– mTOR- p70S6K1 signaling pathway plays important physiological roles in both normal and tumor cell growth and proliferation [
26,
27]. The activation of this signaling pathway may promote cell proliferation, tumor invasion and metastasis through blocking apoptosis [
26,
27]. Our Studies demonstrated that Tan II A inhibited the PI3K- Akt – mTOR - p70S6K1 signal transduction pathway and activated autophagy production. Tan II A was also demonstrated to inhibit the melanoma A375 cell induced tumor progression in the mouse model.