Chemical and genetic inhibition of STAT3 sensitizes hepatocellular carcinoma cells to sorafenib induced cell death

Abstract

Hepatocellular carcinoma (HCC) has become the second leading cause of cancer related death, with an increasing death rate in recent years. For advanced HCC, sorafenib is the first-line FDA approved drug, with no more than 3 months' overall survival advantage. Recently, a novel strategy has been proposed to improve sorafenib efficacy through enhancing the ability of sorafenib to induce cell death. STAT3 plays a key role in cancer development and recurrence by promoting cell proliferation, survival and immune evasion through its well-established function as a transcription factor in cancer. Notably, STAT3 transcription activity, indicated by its phosphorylation on Y705 is heterogeneous in different liver cancer cell lines. And sorafenib attenuates STAT3 phosphorylation on Y705. However, the role of STAT3 in sorafenib induced cell death is still largely unknown. Here, we show that liver cancer cells also exhibit heterogeneous sensitivities to sorafenib induced cell death, which co-relates with the STAT3-Y705 phosphorylation levels and JAK1/2 expression levels in Hep3B, Huh7 and HepG2 cells. Furthermore, overexpression or knockdown of STAT3 could switch HCC cells between resistant and sensitive to sorafenib induced cell death, which could be partially due to its regulation on Mcl-1, an anti-apoptotic protein. Finally, both inhibitors of STAT3 SH2 domain (S3i-201) or STAT3 upstream kinases JAKs (JAK inhibitor I) could synergistically enhance sorafenib induced cell death. Taken together, these data strongly suggest that STAT3 is not only a downstream effector of sorafenib, but also a key regulator of cellular sensitivity to sorafenib induced cell death, which provide support for the notion to develop STAT3-targeting drugs to improve clinical efficacy of sorafenib in liver cancer.

JAK/STAT signaling in hepatocellular carcinoma

“…Inhibition of STAT3 by JAK2 inhibitor, AG490, further induced apoptosis in HCC cell line, Hep3B, by downregulating the expression of anti-apoptotic proteins Bcl-xL and survivin [34]. Additionally, STAT3 has also been implicated in the development of sorafenib resistance in HCC cell line Huh7 by the regulation of anti-apoptotic protein, Mcl-1 [43]. The overexpression of JAK1/2 and constitutive phosphorylation of STAT3 (Tyr705) results in the nuclear localization of STAT3 and expression of Mcl-1 [43].…”

“…Additionally, STAT3 has also been implicated in the development of sorafenib resistance in HCC cell line Huh7 by the regulation of anti-apoptotic protein, Mcl-1 [43]. The overexpression of JAK1/2 and constitutive phosphorylation of STAT3 (Tyr705) results in the nuclear localization of STAT3 and expression of Mcl-1 [43]. Knockdown of STAT3 led to a downregulation of Mcl-1 expression in vitro, rendering the cells sensitive to sorafenib-induced cell death.…”

<p>LncRNA DANCR Promotes Sorafenib Resistance via Activation of IL-6/STAT3 Signaling in Hepatocellular Carcinoma Cells</p>

“…Sustaining activation of IL-6/STAT3 signaling is crucial for sorafenib resistance. [29][30][31] Recent studies reported that PSMD10 could active IL-6/STAT3 signaling by facilitating the phosphorylation of Rb and IL-6 transcription, thereby promoting sorafenib resistance. 10,32 Based on these studies, we speculated that DANCR may have an effect on IL-6/STAT3 signaling via PSMD10.…”

Liraglutide activates nature killer cell-mediated antitumor responses by inhibiting IL-6/STAT3 signaling in hepatocellular carcinoma

“…It has been reported that inhibition of STAT3 sensitizes HCC cells to sorafenib induced tumor cell death [ 37 ]. Similarly, STAT3 activation contributed to regorafenib resistance of HCC [ 38 ].…”