Rapamycin reverses TLR4 signaling-triggered tumor apoptosis resistance by disrupting Akt-mediated Bcl-xL upregulation
Authors: Qiaoling Sun
Qiuyan Liu
Yuanyuan Zheng
Xuetao Cao
Journal: International Immunopharmacology (2008)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Toll-like receptor 4; TLR4 signaling; tumor escape; tumor progression; apoptosis resistance
Affiliations: Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, PR China.

Abstract:  Toll-like receptor 4 (TLR4) signaling in tumor cells can promote tumor escape and tumor progression, for which TLR4-triggered resistance of tumor cells to apoptosis has been proposed as one of the mechanisms. Rapamycin is an immunosuppressant agent widely used for treatment of transplantation rejection and autoimmune diseases, and recently used for cancer therapy. However, the underlying mechanisms responsible for antitumor effects of rapamycin remain to be fully elucidated. Here we report that rapamycin can reverse TLR4-triggered resistance of colon cancer cells to oxaloplatin- or doxorubicin-induced apoptosis by disrupting Akt and subsequent NF-kappaB activation, suppressing upregulation of anti-apoptotic protein Bcl-xL. Furthermore, Akt/NF-kappaB inhibitors also reverses the apoptosis resistance, accordingly, Akt constitutive activation rescues NF-kappaB activation and Bcl-xL expression in rapamycin-pretreated colon cancer cells, suggesting Akt disruption is critical to the process. Therefore, rapamycin may abrogate TLR4-triggered tumor apoptosis resistance by inhibiting Akt/NF-kappaB pathways and Bcl-xL expression, providing experimental evidence for the anti-tumor effect of rapamycin. 

Retracted: No

PubPeer comments:
 Figure 2E. * In the top OXL row, the LPS- and LPS+LY panels appear to share many similarities. * In the bottom DXR row, the LPS+PDTC and LPS+LY panels appear to share many similarities. The panels are not identical, and the gated percentages are different, but some areas, marked in different colors, appear to look unexpectedly similar. ![file] , 
 Figure 3. Four lanes in the Actin panel in Figure 3C look unexpectedly similar to four lanes in the Actin panel of Figure 3E. Shown with blue boxes. There is a little dot between the second and third lane of both sets of 4 lanes. ![file] , 
 #1 One more. ![file] , 
 Figure 2. * In red: the Actin panel in Figure 2C (CT26 cells) looks like the upside-down version of the Actin panel in Figure 2D (HT29 cells). * In green: Seven lanes of the p-IkBa panel in 2C (CT26 cells) look similar to lanes in the p-IkBa panel in Figure 2D (HT29 cells). * In addition, several panels in Figure 2C appear to look very similar to panels in Figure 4 in another paper by the same group, i.e. Sun et al., Molecular Immunology (2008) - doi: 10.1016 j.molimm.2008.01.025. See: https: pubpeer.com publications 34C28C3EC0BE1B2D3B4DF8DDC4BBA0 ![file] , 
 4. Fig2. C and D p-Akt blots are also the same but just flipped upside down , 
 Corrigendum, March 2020, found here: https: www.sciencedirect.com science article pii S1567576920300357  The authors regret errors in Fig. 2C, 2D, 2E, and Fig. 3C, 3E. In these figures, the images of Western blot and Flow cytometry results should be replaced with appropriate images. The figures below are correct. The changes do not affect the scientific conclusion and significance of the article. It is surprising to see the grave concerns about the flow cytometry panels listed in comments #1 and #3 be addressed by replacing the with new versions. How can these be unintentional errors? This is especially baffling in light of the Editorial written by this journal s Editor in Chief, Dr. JE Talmadge, https: www.sciencedirect.com science article pii S1567576920304495, which states  it is the collective responsibility of the research community to ensure scientific integrity, including research validation . Can Dr. Cao please comment on the origin of the repeated parts of the flow cytometry panels? Are these caused by honest errors, and if so, could he please describe in detail how this could have happened? ,