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Zhu et al. Function of Mcl-1 and its regulative relations with HCC

cells with exposure to ursolic acid (UA), western blot effect of XN. In brief, XN mediated growth suppression
results showed decreased expression of the Mcl-1 and of HCC through inhibition of the Notch signaling
that treatment with UA induces apoptosis by inhibition pathway. [63]
of PI3K/Akt and P38/MAPK signaling pathway. [54]
Yu et al. [55] found that Mcl-1 protein expression was Translational regulation
downregulated via inhibition PI3K by LY294002 in The same as Mcl-1 protein, Mcl-1 mRNA have very
HepG2 cells, which indicates that PI3K/Akt signaling short half-lives. Translationally, mir-29b binding to
pathway regulates Mcl-1 expression. Data from two the 3’-untranslated region of Mcl-1 mRNA inhibits
human HCC cell lines, SMMC7721 and HepG2, expression of Mcl-1. [64] Northern blot and real-time
indicated that exogenous rhHPPCn (Hepatopoietin quantitative reverse transcription polymerase chain
Cn) suppressed trichostatin A-induced apoptosis of reaction showed that downregulation of mir-29
HCC cells and up-regulated Mcl-1 expression in HCC- was a frequent event in HCC tissues. Further study
derived cells via the MAPK or sphingosine kinase-1. implicated that mir-29 may promote apoptosis of
[56]
Real-time polymerase chain reaction analysis and HCC cells through directly targeting Bcl-2 and Mcl-1.
western blot results demonstrated that aspirin induced Besides, the ability of HCC cells to form tumor in nude
Mcl-1 expression at mRNA level as well as protein mice was dramatically repressed by induction of mir-
level through Akt/extracellular regulated kinase (ERK) 29. These results indicated that Bcl-2 and Mcl-1 were
1/2 and stimulates AMPK-Akt/ERK1/2-Mcl-1 axis in predominant mediators of mir-29 promoted apoptosis
HepG2 cells. [57] P53 as a tumor suppressor protein also in HCC cells. [65] The mammalian target of rapamycin
involves the regulation of Mcl-1. It has been reported complex 1 (mTORC1) is a protein complex whose role
that mutation in the P53 frequently occurred in HCC is to activate translation of proteins just like a nutrient
and contributed to hepatocarcinogenesis as well as sensor controlling protein synthesis and a downstream
apoptosis resistance. [58] Additionally, Leu et al. [59] target of PI3K/Akt. [66] There was a report that described
demonstrated that P53 antagonized the interactions that activation of mTORC1 was of vital importance to
between Mcl-1 and Bak. Once mutation happens be a potent antiapoptotic signal through Mcl-1 which
in HCC, Mcl-1 couldn’t be dissociated from Bak and is a translationally regulated genetic determinant of
the final result is apoptosis resistance of hepatoma mTORC1-dependent survival. [67] And a recent study
cells. Data from human samples showed that P53 demonstrated that metformin-induced apoptosis in
protein was also overexpressed in HCC tissues and HCC was mediated by the downstream mTORC1
its expression was significantly correlated with Mcl-1 effectors eukaryotic initiation factor 4E (eIF4E) and
expression. Further research indicated that silencing eIF4E-binding proteins who were required to induce
Mcl-1 sensitizes hepatoma cells towards chemotherapy apoptosis by metformin in HCC and to repress Mcl-1
may be attributed to the dysfunction of P53 through expression. [68]
Mcl-1/P53 interaction. [55] According to combination of
ICG-001, a small molecule which blocks the interaction Post-translational regulation
of β-catenin with its transcriptional coactivator CREB-
binding protein, and sorafenib to treat several HCC cell There is variety of modes regulating Mcl-1 at post-
lines, the effect was a significant downregulation of Mcl- translational level. In the preceding part of this review,
1 which was the most consistent change across tested we have mentioned that the PEST region of Mcl-1
HCC cell lines. The author concluded that the sorafenib- was rich in putative phosphorylation sites which made
sensitizing effect of Wnt/β-catenin pathway inhibition Mcl-1 different from other Bcl-2 family members.
was closely associated with Mcl-1 downregulation in Here, we detail those phosphoresidues of Mcl-1 and
HCC cells. [60] In addition, recent reports described that the influence of phosphorylation in HCC. Both of the
Wnt/β-catenin signaling could regulate Mcl-1 expression phosphoresidues Threonine 92 and Threonine 163
indirectly, involving genes regulated by Wnt/β-catenin of Mcl-1 were identified by Ding et al. [69] using ERK-
pathway or other transcriptional factors. [61,62] Moreover, 1 kinase assay. ERK-1 phosphorylation of Thr 92 and
a panel of HCC cell lines has been on treatment with Thr 163 stabilizes Mcl-1 and then promotes Mcl-1’s
Xanthohumol (XN), a prenylated chalcone having anti-apoptosis. It has been demonstrated that heat
anti-proliferative effects in various cancers types in shock protein 90 inhibitor 17-allylaminogeldanamycin
vitro, and growth suppression due to apoptosis was (17-AAG) partially inversed (-)-gossypol-induced Mcl-
evidenced by reduced expression of anti-apoptotic 1 accumulation by inhibiting ERK phosphorylation in
proteins including Mcl-1. Importantly, XN treatment HCC cells. [70] Of note, Inoshita et al. [71] concluded that
decreased the expression of Notch1 and hairy and phosphorylation of Thr 163 by JNK destabilized Mcl-
enhancer of split-1 proteins while ectopic expression 1, whereas the results showed by Kodama et al. [72]
of Notch1 in HCC cells abolished the anti-proliferative suggested that C-Jun N-terminal kinase (JNK) as the

Hepatoma Research ¦ Volume 3 ¦ July 06, 2017 133