Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma
Background: Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while the accurate effect is vague. Methods: The efficacy of combinations between oxaliplatin and anti-cancer molecular targeting drugs was screened. Strangely, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Then the antitumor effects of combined treatment with saracatinib and oxaliplatin were confirmed in wide type HCC as well as in saracatinib- and oxaliplatin-resistant HCC. RNA sequencing was used to explore the resistance mechanism, and the roles of ABCG1 and Wnt signaling in oxaliplatin resistance were confirmed. Results: Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. And it was saracatinib treatment caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding the ATP-binding cassette transporter G1 ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in HCC. Conclusions: These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the activation of Wnt signaling and upregulation of ABCG1 by saracatinib.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
This is a list of supplementary files associated with this preprint. Click to download.
Posted 03 Jan, 2020
On 13 Jan, 2020
On 18 Dec, 2019
On 18 Dec, 2019
On 16 Dec, 2019
On 13 Dec, 2019
On 12 Dec, 2019
On 12 Dec, 2019
On 09 Dec, 2019
On 08 Dec, 2019
On 07 Dec, 2019
On 07 Dec, 2019
On 26 Nov, 2019
Received 23 Nov, 2019
Received 19 Nov, 2019
On 10 Nov, 2019
Invitations sent on 05 Nov, 2019
On 05 Nov, 2019
On 30 Oct, 2019
On 29 Oct, 2019
On 29 Oct, 2019
On 21 Oct, 2019
Received 13 Oct, 2019
Received 30 Aug, 2019
Received 21 Aug, 2019
On 17 Aug, 2019
On 16 Aug, 2019
On 22 Jul, 2019
Invitations sent on 22 Jul, 2019
On 27 Jun, 2019
On 12 Jun, 2019
On 12 Jun, 2019
On 30 May, 2019
Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma
Posted 03 Jan, 2020
On 13 Jan, 2020
On 18 Dec, 2019
On 18 Dec, 2019
On 16 Dec, 2019
On 13 Dec, 2019
On 12 Dec, 2019
On 12 Dec, 2019
On 09 Dec, 2019
On 08 Dec, 2019
On 07 Dec, 2019
On 07 Dec, 2019
On 26 Nov, 2019
Received 23 Nov, 2019
Received 19 Nov, 2019
On 10 Nov, 2019
Invitations sent on 05 Nov, 2019
On 05 Nov, 2019
On 30 Oct, 2019
On 29 Oct, 2019
On 29 Oct, 2019
On 21 Oct, 2019
Received 13 Oct, 2019
Received 30 Aug, 2019
Received 21 Aug, 2019
On 17 Aug, 2019
On 16 Aug, 2019
On 22 Jul, 2019
Invitations sent on 22 Jul, 2019
On 27 Jun, 2019
On 12 Jun, 2019
On 12 Jun, 2019
On 30 May, 2019
Background: Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while the accurate effect is vague. Methods: The efficacy of combinations between oxaliplatin and anti-cancer molecular targeting drugs was screened. Strangely, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Then the antitumor effects of combined treatment with saracatinib and oxaliplatin were confirmed in wide type HCC as well as in saracatinib- and oxaliplatin-resistant HCC. RNA sequencing was used to explore the resistance mechanism, and the roles of ABCG1 and Wnt signaling in oxaliplatin resistance were confirmed. Results: Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. And it was saracatinib treatment caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding the ATP-binding cassette transporter G1 ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in HCC. Conclusions: These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the activation of Wnt signaling and upregulation of ABCG1 by saracatinib.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5