Type 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells

Abstract

Although the involvement of type 1 (IP3R1) and type 2 (IP3R2) inositol 1,4,5-trisphosphate receptors in apoptosis induction has been well documented in different cancer cells and tissues, the function of type 3 IP3R (IP3R3) is still elusive. Therefore, in this work we focused on the role of IP3R3 in tumor cells in vitro and in vivo. We determined increased expression of this receptor in clear cell renal cell carcinoma compared to matched unaffected part of the kidney from the same patient. Thus, we hypothesized about different functions of IP3R3 compared to IP3R1 and IP3R2 in tumor cells. Silencing of IP3R1 prevented apoptosis induction in colorectal cancer DLD1 cells, ovarian cancer A2780 cells, and clear cell renal cell carcinoma RCC4 cells, compared to apoptosis in cells treated with scrambled siRNA. As expected, silencing of IP3R3 and subsequent apoptosis induction resulted in increased levels of apoptosis in all these cells. Further, we prepared a DLD1/IP3R3_del cell line using CRISPR/Cas9 gene editing method. These cells were injected into nude mice and tumor's volume was compared with tumors induced by DLD1 cells. Lower volume of tumors originated from DLD1/IP3R3_del cells was observed after 12 days, compared to wild type DLD1 cells. Also, the migration of these cells was lesser compared to wild type DLD1 cells. Apoptosis under hypoxic conditions was more pronounced in DLD1/IP3R3_del cells than in DLD1 cells. These results clearly show that IP3R3 has proliferative and anti-apoptotic effect in tumor cells, on contrary to the pro-apoptotic effect of IP3R1.

Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

“…An increased expression of ITPR3 was detected in clear renal cell carcinoma compared to the unaffected part of the kidney [81]; ITPR3 silencing affected tumor growth, in vitro as well as in vivo, providing a direct proof of the involvement of this receptor in the carcinogenesis. An increased expression of ITPR3 has been also observed in cholangiocarcinoma [82] and in colorectal cancer [83]; in both cases the expression of ITPR3 correlated with the degree of neoplasia severity [82,83].…”

Osthole interacts with an ER‐mitochondria axis and facilitates tumor suppression in ovarian cancer

“…IP3R is pivotal for physiological mechanisms in cell growth, development, division, apoptosis, and fertilization (Bosanac et al, 2002). Silencing of IP3R1 inhibits cell apoptosis in colorectal cancer DLD1 cells, ovarian cancer A2780 cells, and clear cell renal cell carcinoma RCC4 cells (Rezuchova et al, 2019). In the present study, IP3R1 and IP3R2 were rarely observed in ES2 and OV90 cells.…”

Lessons from the Endoplasmic Reticulum Ca2+ Transporters—A Cancer Connection

“…Besides the functional regulation of IP 3 Rs by the oncoprotein-tumor suppressor crosstalk, the selective expression of individual IP 3 R isoform has also been tampered with in several clinical malignancies. For instance, IP 3 R3 is up-regulated in gastric cancer, glioblastoma and renal cell carcinoma [ 117 , 118 , 119 ]. Additionally, IP 3 R3 expression level has been found increased and positively correlated with the migratory and invasive capacities of breast cancer and glioblastoma cell lines and that caffeine-mediated IP 3 R3 inhibition abrogated proliferative and invasive phenotypes in glioblastoma and extended survival rate [ 120 , 121 ].…”