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CANCER STEM CELLS AND
ONCOLOGY RESEARCH
11
th
International Conference on
Journal of Medical Oncology and Therapeutics
|
Volume 3
ELUCIDATING
THE UNDERLYING
MECHANISM OF CSC
ENRICHMENT BY
PLATINUM TREATMENT
IN EPITHELIAL OVARIAN
CANCER CELLS: A STORY
JUST BEGINS TO UNFOLD
Aniketh Bishnu, Asmita Sakpal and Pritha Ray
ACTREC, India
H
igh grade serous epithelial ovarian cancer (HGSOC) is
notoriously known for high recurrence and mortality
due to acquirement of chemoresistance. Both chemonaive
and platinum sensitive relapse cases of HGSOC patients
are treated with cisplatin/carboplatin with or without other
drugs as a standard therapy regime for last two decades.
Unfortunately, both cases eventually develop platinum re-
sistance and succumb to the disease. Whether and how re-
petitive exposure of platinum drugs in cancer cells creates
enriched drug resistant cancer stem cells like fate has not
been explored in detail. To decipher this molecular mech-
anism, we looked into IGF1R-PIK3CA-AKT signalling path-
way alteration during acquirement of platinum resistance
in indigenously developed chemoresistant cellular models.
Increased CSC-marker expression, side population, spher-
oid formation were observed during the course of resis-
tance acquirement. Interestingly, CSC like SP cells which
are in early phase of resistance development demonstrated
faster tumorigenic potential than CSC like SP cells isolated
from late resistant phases (Singh et al, Scientific Reports,
2016). This late resistant cells contain maximal percent-
age of CSCs and other characteristics of stem cells. Us-
ing a DNA-protein pull down assay, we identified NF-B as a
prime transcriptional regulator of PIK3CA-Akt signalling in
these late cisplatin resistant cells and their corresponding
SP cells after cisplatin treatment. Along with PIK3CA, NF-
κB also escalated TNFα expression specifically in SP frac-
J Med Oncl Ther 2018, Volume 3
tion upon cisplatin treatment. Our data conclusively showed
that this CSC-specific NF-κB-TNFα-PIK3CA bi-modal loop, on
one hand, maintains persistent activation of NF-κB through
TNFα- NF-κB autocrine loop, while NF-κB-PIK3CA loop nur-
tures CSC population under cisplatin treatment. Overall, ac-
tivation of PI3K/AKT and NF-κB signaling in resistant cells
favours survival and enrichment of CSCs by acquiring an-
ti-apoptotic, quiescent state (Thakur and Ray, J. of Exp. Clin.
Cancer Res., 2017). In order to explore a mode to inhibit en-
richment of CSC with progression of resistance, we developed
chemoresistant cellular model treated with platinum-taxol
along with Metformin, a known anti-diabetic drug. Intriguingly,
concurrent treatment of metformin with platinum-taxol signifi-
cantly reduced the CSC like side population (32% vs. 10%) and
the resistance properties (92% to 70%) of these cells. Further
studies are ongoing to understand the alleviating effect of
Metformin on platinum resistance with a special emphasis on
NF-B-TNFα-PIK3CA bi-modal loop present in platinum resis-
tant ovarian cancer cells.
pray@actrec.gov.in